The human nervous system consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS contains the brain and spinal cord. The PNS comprises the nerve fibers that connect the CNS to every other part of the body. The PNS includes the motor neurons that are responsible for mediating voluntary movement. The PNS also includes the autonomic nervous system which encompasses the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. The sympathetic and parasympathetic nervous systems are tasked with the regulation of all involuntary activities. The enteric nervous system is unique in that it represents a semi-independent part of the nervous system whose function is to control processes specific to the gastrointestinal system. The nervous systems of the body are composed of two primary types of cell: the neurons that carry the chemical signals of nerve transmission, and the glial cells that serve to support and protect the neurons.

Two important concepts relate to the functioning of the nervous system. These terms are efferent andafferent. Efferent connections in the nervous system refer to those that send signals from the CNS to the effector cells of the body such as muscles and glands. Efferent nerves are, therefore, also referred to as motor neurons. Afferent connections refer to those that send signals from sense organs to the CNS. For this reason these nerves are commonly referred to as sensory neurons.

Another important cellular structure in nervous systems are the ganglia. The term ganglion refers to a bundle (mass) of nerve cell bodies. In the context of the nervous system, ganglia are composed of soma (cell bodies) and dendritic structures. The dendritic trees of most ganglia are interconnected to other dendritic trees resulting in the formation of a plexus. In the human nervous system there are two main groups of ganglia. The dorsal root ganglia, which is also referred to as the spinal ganglia, contains the cell bodies of the sensory nerves. The autonomic ganglia contain the cell bodies of the nerves of the autonomic nervous system. Nerves that project from the CNS to autonomic ganglia are referred to as preganglionic nerves (or fibers). Conversely, nerves projecting from ganglia to effector organs are referred to as postganglionic nerves (or fibers). Generally the term ganglion relates to the peripheral nervous system. However, the term basal ganglia (also basal nuclei) is used commonly to describe the neuroanatomical region of the brain that connects the hypothalamus, cerebral cortex, and the brainstem.

Neurons are the highly specialized cells of all nervous systems (e.g. CNS and PNS) that are tasked with transmitting signals from one location to another. These cells accomplish this role through specialized membrane-to-membrane junctions called synapses. Most neuron possess an axon which is a long protrusion from the body (soma) of the neuron to the synapse. Axons can extend to distant parts of the body and make thousands of synaptic contacts such as is the case with the CNS neurons of the spinal cord. Axons frequently travel through the body in bundles called nerves. The synapses are termed pre-synaptic and post-synaptic. The pre-synaptic synapse will release secretory granule contents in response to the propagation of an electrochemical signal (action potential) down its axon. The released substance (termed a neurotransmitter) will then, most likely, bind to a specific receptor on the membrane of the post-synaptic synapse, thereby, propagating the initial action potential to the next neuron. The human nervous system is composed of hundreds of different types of neurons. These include sensory neurons that transmute physical stimuli such as light and sound into neural signals, and motor neurons that are responsible for converting neural signals into activation of muscles or glands.

Glial cells (named from the Greek for "glue") are the specialized non-neuronal cells of the nervous system that provide protection, support and nutrition for neurons. As the Greek name glue infers, glial cells hold neurons in place and provide guidance cues which directs axons of the neurons to their appropriate target cell(s). Glial cells are responsible for the maintenance of neural homeostasis, for the formation of myelin, and they play a participatory role in signal transmission in the nervous system. Glial cells provide an electrical insulation (myelin) for neurons which allows for rapid transmission of action potentials and also prevents the abnormal propagation of nerve impulses to inappropriate neurons. The glial cells that produce the myelin sheath are called oligodendrocytes in the CNS and Schwann cells in the PNS. Glial cells also destroy pathogens and remove dead neurons.

The sympathetic nervous system (SNS) is predominantly responsible for excitatory action potentials with the goal of inducing the "fight-or-flight" responses of the body under conditions of stress. In general, activation of the SNS results in contraction, for example, vasoconstriction. Although stress is a major trigger of the SNS, it is constantly active at a basal level to maintain homeostasis. The activation of the neurons of the SNS occurs as a result of signals arising in the region of the brain stem called the nucleus of the solitary tract (NTS, for the latin term nucleus tractus solitarii). The NTS receives a wide range of sensory inputs from both systemic and central baroreceptors and chemoreceptors. The neurons of the SNS emanate from the medulla, specifically the rostral ventrolateral medulla, and travel down the spinal cord where they synapse with short preganglionic neurons within the sympathetic ganglia. The ganglia of the SNS are the nerve cell bodies that lie on either side of the spinal cord. Preganglionic sympathetic fibers are those that exit the spinal cord synapses within these ganglia. The preganglionic neurotransmitter is acetylcholine, ACh. ACh released from the sympathetic preganglionic neuron binds to nicotinic ACh receptors (nAChR) on the postganglionic neuron. ACh binding depolarizes the cell body of the postganglionic neuron generating an action potential that travels to the target organ to elicit a response. The neurotransmitter released from sympathetic postganglionic neurons is norepinephrine which binds to its receptor expressed in the target cell. The target organ receptors responsive to signals from the SNS are those of the adrenergic family, specifically 1, 2, 1, and 2 (see below). Although the primary neurotransmitter released from sympathetic postganglionic neurons is norepinephrine, there are two important exceptions. These exceptions are the postganglionic neurons that innervate chromaffin cells of the adrenal medulla and those that innervate the sweat glands. When the postganglionic neurons that innervate sweat glands are activated, they release ACh (not epinephrine) which binds to muscarinic ACh receptors (mAChR: specifically the M1 and M3 receptors) on the target cell. Adrenal medullary chromaffin cells are functionally analogous to sympathetic postganglionic neurons and when stimulated by ACh from a sympthetic preganglionic neuron these cells release epinephrine and norepinephrine into the circulation. The receptors triggering the release of adrenal epinephrine and norepinephrine are nicotinic (nAChR).

The parasympathetic nervous system is predominantly responsible for inhibitory action potentials resulting in relaxation, for example, vasodilation. The parasympathetic nervous system is responsible for stimulation of "rest-and-digest" and "feed-and-breed" activities that occur when the body is at rest. These responses include, but are not limited to, sexual arousal, salivation, lacrimation (tears), urination, digestion and defecation. Within the head the parasympathetic nervous system includes cranial nerves III, VII, and IX while cranial nerve X (comprising the vagus nerves) exits the brain stem to innervate the organs of the body. Like the SNS, the activation of the vagus nerves of the parasympathetic nervous system occurs as a result of signals arising in the NTS. There are three nuclei within the medulla that send out vagal nerves of the parasympathetic nervous system. These nuclei are the dorsal motor nucleus, the solitary nucleus, and the nucleus ambiguus. Parasympathetic neural outputs to the heart arise primarily within the nucleus ambiguus. The ganglia of the parasympathetic nervous system are also referred to as terminal ganglia as they lie close to, or within, the organs that they innervate. The exceptions to this are the parasympathetic ganglia of the head and neck. Parasympathetic ganglia are those that are found within the target organ. Preganglionic parasympathetic fibers associated with the vagal nerve all exit the brain stem, they do not travel down the spinal chord except for the pelvic splanchnic nerves which exit the spinal cord in the S2-S4 region. The parasympathetic preganglionic nerves enter their target organs where they form synapses with postganglionic neurons. Like the sympathetic ganglia, the neurotransmitter of parasympathetic preganglionic nerves is ACh. When released from these nerves the ACh binds to nicotinic ACh receptors (nAChR) on the postganglionic nerve. However, unlike sympathetic postganglionic nerves, activation of the parasympathetic postganglionic nerves results in the release of ACh. When released from the parasympathetic postganglionic neuron, the ACh binds to muscarinic ACh receptors (mAChR) in the target cells, primarily the M2 and M3 receptors.

Within the cardiovascular system the norepinephrine released from sympathetic postganglionic neurons binds to 1 (and to a lesser extent 2) adrenergic receptors expressed on cardiac myocytes of the heart within the sinoatrial (SA) node (primary cardiac pacemaker cells), the atrioventricular (AV) node, the ventricles, and the Purkinjie fibers of the cardiac conduction system. Activation of the 1 receptor in the heart results in increased force of contraction (inotropy), increased heart rate (chronotropy), and increased cardiac conductance (dromotropy). These effects are exerted as a result of the increased levels of cAMP and the activation of PKA that result from 1 receptor activation of Gs-type G-proteins.

Activation of the 1 receptor associated Gs-type G-proteins results in the consequent activation of adenylate cyclases. The major adenylate cyclases activated by -adrenergic receptors in the heart are encoded by the ADCY5 and ADCY6 genes. The ADCY5 encoded enzyme, identified as AC5 is localized to the nuclear membrane and to specialized domains of the membranes of the T-tubule system of the cardiac myocyte. AC5 activity is regulated by both 1- and 2-adrenergic receptors in cardiac myocytes. The ADCY6 encoded enzyme, midentified as AC6, is localized to the sarcolemma (muscle cell plasma membrane) of the cardiac myocyte outside the T-tubule system. AC6 activity is regulated exclusively by 1-adrenergic receptors. The extent to which cAMP can exert its effects, either directly or through the activation of PKA, is controlled by the receptor-mediated activation of these adenylate cyclases as well as by the activities of various enzymes of the phosphodiesterase (PDE) family. Multiple PDE isoforms are expressed within various tissues of the heart, however, within the cardiac myocyte the predominate PDE are members of the PDE4D family, specifically the PDE4D5 and PDE4D8 isoforms. However, it should be noted that members of the PDE2 and PDE3 families are also expressed within cardiac myocytes. The PDE4D8 isoform is localized to protein complexes at the sarcolemma (plasma membrane) that includes the 1-adrenergic receptor.

Numerous responses, exerted by -adrenergic receptor activation, are the result of cAMP itself. Direct effects of cAMP within cardiac myocytes of the SA node, AV node, and the Purkinje fibers contribute to positive chronotropic and dromotropic effects ellicited as a result of 1-adrenergic receptor activation. The effects of direct cAMP action include binding to, and modulation of the activity of the hyperpolarization-activated cyclic nucleotide-gated channel 2 and 4 (HCN2 and HCN4; often referred to as funny current channels) resulting in positive chronotropic and dromotropic activities of the cardiac myocytes. Another important protein activated by direct nteraction with cAMP is RAP guanine nucleotide exchange factor 3 (encoded by the RAPGEF3 gene). The RAPGEF3 encoded protein was originally, and is commonly, referred to as exchange protein directly activated by cAMP, EPAC (also known as EPAC1). The activation of EPAC by cAMP results in the activation of Ca2+/calmodulin kinase II (CaMK2). When activated, CaMK2 phosphorylates the calcium release channel, ryanodine receptor 2, RYR2, resulting in increased release of Ca2+ stored within the sarcoplasmic reticulum, SR. Increased free intracellular Ca2+ plays a major role in the contractile activity of muscle cells. Thus, the stimulated release of Ca2+ from the SR contributes to the increased inotropic and chronotropic effects of 1-adrenergic receptor activation. Activation of EPAC also results in the downregulation of the regulatory subunit of voltage-gated potassium channels which are commonly identifed as Kv channels. The regulatory subunit of the Kv channels is encoded by the KCNE1 gene and is commonly referred to as the -subunit. The specific cardiac Kv family channels that are regulated by the KCNE1 encoded protein are Kv2.1 channels encoded by the KCNB1 gene and Kv1.9 channels encoded by the KCNQ1 gene. The KCNQ1 potassium channels, and to a lessor extent the KCNB1 channels, are required for the repolarization phase of cardiac myocyte action potentials.

Within the cardiac myocyte PKA is localized to specific subcellular locations through its anchoring to proteins of the A-kinase anchoring protein (AKAP) family. Upon its activation via cAMP, PKA mediates its effects on cardiac contractility and chronotropy via the phosphorylation of numerous proteins controlling these processes. PKA phosphorylates L-type Ca2+ channels in the plasma membrane (sarcolemma) and RYR2 in the sarcoplasmic reticulum (SR). The PKA-mediated phosphorylation of plasma membrane Ca2+ channels results in increased influx of Ca2+ and the phosphorylation of the RYR2 channel results in increase release of Ca2+ stored in the SR. Both of these events lead to increased Ca2+ availability for activation of the calmodulin subunit of myosin light-chain kinase, MLCK. The released Ca2+ also interacts with troponin C (TnC) resulting a conformational change to the troponin complex (troponin C, I, and T) that moves the attached tropomyosin away from the myosin binding sites on actin. This conformational change abolishes the inhibitory action of the TnI protein of the complex. In addition, the conformational change permits nearby myosin heads to interact with myosin binding sites, and contractile activity ensues. PKA also phosphorylates troponin I preventing it from inhibiting the interactions of actin and myosin. Another important target of PKA is the protein identified as phospholamban (PLN). Phospholamban interacts with SR membrane-associated Ca2+ reuptake channels identified as sarco/endoplasmic reticulum Ca2+-ATPases (SERCA: encoded by ATP2A family genes). The cardiac myocyte SERCA is identified as SERCA2A and is encoded by the ATP2A2 gene. The normal function of PLN is to inhibit the reuptake of Ca2+ into the SR via the action of SERCA2A transporters. Phosphorylation of PLN by PKA reduces the inhibitory action of PLN on SERCA2A promoting Ca2+ reuptake. Diastolic relaxation of cardiac myocytes requires Ca2+ reuptake by the SR, thus, the inhibition of PLN allows for an increased rate of myocyte contraction and relaxation resulting in an overall increased force of contraction.

Within the cardiac vasculature, sympathetic postganglionic nerve release of norepinephrine results in activation of the 1 and 2 adrenergic receptors in the smooth muscle cells resulting in vasoconstriction. However, the smooth muscle cells of the vessels in skeletal muscle possess predominantly 2 adrenergic receptors, stimulation of which results in vasodilation, since they need to remain open to receive the increased blood flow from the heart during the fight-or-flight response. The primary activator of the 2 adrenergic receptors in skeletal muscle vasculature is the epinephrine released from the adrenal medulla in response to sympathetic activation.

Within the cardiovascular system the primary target cells of the heart that receive parasympathetic innervation are the SA node (from the right vagus nerve), the AV node (from the left vagus nerve), and atrial cells. The cardiac muscarinic receptor that binds the ACh released from parasympathetic postganglionic nerves is the M2 type receptor. Each of the muscarinic ACh receptors is a GPCR and the M2 receptors are coupled to a Gi-type G-protein. Activation of the M2 receptor results in decreased levels of cAMP leading to reduced direct effects of cAMP and reduced activation of PKA, thereby reducing all of the processes discussed above. Activation of the M2 receptor also results in the activation of membrane K+ channels resulting in rapid hyperpolarization of cardiac myocytes leading to termination of an action potential. The particular class of K+ channels that are responsive to G-proteins are activated by the subunits of the G-protein. These K+ channels are commonly referred to as G protein-coupled inwardly-rectifying potassium channels (GIRK). The GIRK are members of the KCNJ subfamily of voltage-gated K+ channels. The net effect of M2 activation is decreased heart rate (chronotropy) and decreased cardiac conductance (dromotropy). The effects of the parasympathetic nervous system on the heart supercede the effects of the sympathetic nervous system such that even in the face of sympathetic stimulation, parasympathetic stimulation can depress cardiac activity. Within the vasculature ACh binds to the M3 receptor on endothelial cells leading to increased NO production resulting in vasodilation. However, this ACh is not derived from parasympathetic nerves but directly from the circulation. Parasympathetic postganglioninc ACh does stimulate M3 receptor-mediated NO production but this is only seen in the external genitalia.

Neurotransmitters are endogenous substances that act as chemical messengers by transmitting signals from a neuron to a target cell across a synapse. Prior to their release into the synaptic cleft, neurotransmitters are stored in secretory vesicles (called synaptic vesicles) near the plasma membrane of the axon terminal. The release of the neurotransmitter occurs most often in response to the arrival of an action potential at the synapse. When released, the neurotransmitter crosses the synaptic gap and binds to specific receptors in the membrane of the post-synaptic neuron or cell.

Neurotransmitters are generally classified into two main categories related to their overall activity, excitatory or inhibitory. Excitatory neurotransmitters exert excitatory effects on the neuron, thereby, increasing the likelihood that the neuron will fire an action potential. Major excitatory neurotransmitters include glutamate, epinephrine and norepinephrine. Inhibitory neurotransmitters exert inhibitory effects on the neuron, thereby, decreasing the likelihood that the neuron will fire an action potential. Major inhibitory neurotransmitters include GABA, glycine, and serotonin. Some neurotransmitters, can exert both excitatory and inhibitory effects depending upon the type of receptors that are present.

In addition to excitation or inhibition, neurotransmitters can be broadly categorized into two groups defined as small molecule neurotransmitters or peptide neurotransmitters. Many peptides that exhibit neurotransmitter activity also possess hormonal activity since some cells that produce the peptide secrete it into the blood where it then can act on distant cells. Small molecule neurotransmitters include (but are not limited to) acetylcholine, GABA, amino acid neurotransmitters, ATP and nitric oxide (NO). The peptide neurotransmitters include more than 50 different peptides. Many of the gut-derived and hypothalamic neurotransmitter peptides are discussed in detail in the Gut-Brain Interrelationships page. Several peptide neurotransmitters are all derived from the same precursor protein, pro-opiomelanocortin (POMC), as discussed in the Peptide Hormones page.

Many neurotransmitters can also be divided into two broad categories dependent upon whether the receptor activated by the binding of transmitter is a metabotropic or an ionotropic receptor. Metabotropic receptors activate signal transduction upon transmitter binding similar to many peptide hormone receptors which involves a second messenger. Metabotropic receptors are members of the G-protein coupled receptor (GPCR) family. Ionotropic receptors ligand-gated ion channels. Some neurotransmitters, for example glutamate and acetylcholine, bind to multiple receptors some of which are metabotropic and some of which are ionotropic.

The transmission of an efferent signal from the CNS to a target tissue, or an afferent signal from a peripheral tissue back to the CNS occurs as a result of the propagation of action potentials along a nerve cell. Nerve cells are excitable cells and they can respond to various stimuli such as electrical, chemical, or mechanical. When the excitation event is propagated along the nerve cell membrane it is referred to as a nerve impulse or more often as an action potential. When a nerve cell terminates on another it does so at a specialized structure called a synapse. Synaptic transmission refers to the propagation of nerve impulses (action potentials) from one nerve cell to another. The synapse is a junction at which the axon of the presynaptic neuron terminates at some location upon the postsynaptic neuron. The end of a presynaptic axon, where it is juxtaposed to the postsynaptic neuron, is enlarged and forms a structure known as the terminal button (pronounced "boo-tawn"). An axon can make contact anywhere along the second neuron: on the dendrites (an axodendritic synapse), the cell body (an axosomatic synapse) or the axons (an axo-axonal synapse).

Action potentials are the result of membrane depolarization which is brought about by a change in the distribution of ions across the membrane. Differences in ion concentrations on either side of a membrane result in a electrical charge differential across the membrane which is referred to as an electrochemical potential. Changes in ion concentrations on either side of a membrane result in depolarization of the membrane. Once a portion of a membrane is depolarized, the ion gradients need to be returned to the "resting" state, a process referred to as repolarization. The movement of ions across the membrane is the function of proteins and protein complexes termed ion channels. Because nerve transmission involves changes in voltage (charge) across the plasma membrane, these ion channels respond to the voltage changes and are, therefore, referred to as voltage-gated ion channels.

The resting membrane potential of a neuron is maintained by the differential distribution of K+ and Na+ ions. The concentration of intracellular K+ is much higher than the extracellular concentration. This situation is just the opposite for Na+, which is at a much higher concentration outside the cell than inside. This differential is maintained through the action plasma membrane transporters of the Na+,K+-ATPase family. The initiation and propagation of an action potential is the result of the opening and closing of voltage-gated K+ channels and voltage-gated Na+ channels. In the rested stated both types of voltage-gated channels are closed. In response to a depolarizing signal (an excitation signal) the fast acting voltage-gated Na+ channels open allowing an influx of Na+ ions into the cell. The influx of Na+ causes more voltage-gated Na+ channels to open propagating the depolarization event. The Na+ channels ultimately close (within milliseconds) to an inactivated state, meaning they cannot be re-opened prior to the membrane returning to its initial rested state. The opening of voltage-gated K+ channels occurs much slower than for the Na+ channels and they are not fully open until the Na+ channels have re-closed. The opening of the K+ channels allows K+ to exit the cell which brings the net charge inside the cell back to the rested state potential. The opening of the K+ channels, following closure of the Na+ channels, represents the repolarization stage and brings the action potential to an end.

Nerve impulses are transmitted from one neuron to another, or from a neuron to a target tissue cell, at synapses by the release of neurotransmitters. As discussed in detail throughout this page, neurotransmitters can be small chemicals, such as amino acids or amino acid derivatives, or they can be lipids, such as the endocannabinoid, anandamide. As a nerve impulse, or action potential, reaches the end of a presynaptic axon, molecules of neurotransmitter are released into the synaptic space. The release of neurotransmitter involves the processes of exocytosis. When an action potential reaches the presynaptic terminal the membrane depolarization results in the opening of voltage-gated Ca2+ channels. The influx of Ca2+ ions induces the membranes of neurotransmitter secretory vesicles to fuse with the plasma membrane allowing the contents to be released into the synaptic cleft.

Glutamate synapse. Structure of a typical synapse showing the presynaptic terminal and the postsynaptic terminal for a typical glutamatergic neural connection. This example depicts a synapse which involves glutamate activation of the three classes of ionotropic glutamate receptors. Definitions of the receptors types can be found in the section below discussing the glutamate-glutamine cycle in the brain.

In order to move a skeletal muscle cell, an action potential must be initiated from a peripheral motor neuron. Cardiac muscle (myocardial) cells on the other hand, can initiate their own electrical activity in the absence of an autonomic nerve-mediated action potential. With respect to skeletal muscle, nerve transmission occurs when an axon of a post-ganglionic nerve terminates on a skeletal muscle fiber, at specialized structures called the neuromuscular junction. An action potential occurring at this site is known as neuromuscular transmission. At a neuromuscular junction, the axon subdivides and branches into numerous structures, referred to as terminal buttons (pronounced "boo-tawns") or end bulbs, that can then innervate numerous skeletal muscle fibers. The result is that many muscle fibers can be innervated by a single neuron instead of each fiber having to be dependent upon an individual neuron for contractile activation. The skeletal muscle fibers that are innervated by branches from the same neuron constitute a motor unit. Large muscles in the body (e.g. the gastrocnemius) contain numerous motor units. This arrangment of the motor units in a particular muscle allows for activation of only a specific part of a muscle at any given time. This represents a form of spatial control over muscle fiber contraction within a muscle, a feature not associated with cardiac muscle excitation as discussed below.

The terminal buttons (end bulbs) of the motor neurons reside within depressions formed in the skeletal muscle plasma membrane (sarcolema). At these locations the skeletal muscle membrane is thickened and is referred to as the motor end plate. The space between the terminal buttons (end bulbs) and the motor end plate is similar to the synaptic cleft that exists where the pre-synaptic and post-synaptic membranes of neurons are in close proximity. The particular neurotransmitter in use at the neuromuscular junction is acetylcholine, ACh. When an action potential reaches the pre-synaptic membrane of a motor neuron the permeability of the membrane changes. This change in permeability allows Ca2+ to enter the nerve endings triggering exocytosis of ACh-containing vesicles. The released ACh then binds to nicotinic ACh receptors (nAChR) that are concentrated in the motor end plate membrane. Once released from the motor neuron, the level of active ACh is controlled by its catabolism through the action of acetylcholinesterase. As discussed below, nAChR are members of the ionotropic receptor superfamily (ion channel receptors). Activation of nicotinic ACh receptors in the motor end plate results in an increase in Na+ and K+ conductance through the nAChR channel. The resulting influx of Na+ into the skeletal muscle cell produces a depolarizing potential. As a result of this depolarization, action potentials are conducted in both directions, away from the motor end plate, along the muscle fiber. These action potentials are the result of the initial membrane depolarization and propagated across the surface membrane via the opening of voltage-gated Na+ channels. The action potential is then propagated down the T-tubule system which directly interacts with the sarcoplasmic reticulum, SR. Activation of the SR leads to the release, into the sarcoplasm (cytoplasm of muscle cells), of stored Ca2+ through the opening of Ca2+ release channels. The SR calcium release channels are also known as the ryanodine receptor (RYR) due to the fact that they were originally identified by their high affinity for the plant alkaloid ryanodine.The end result of the ACh-initiated propagating action potential is muscle contraction.

A particularly devastating disease that results from defects in the overall processes of neuromuscular nerve transmission is myasthenia gravis, MG. MG is a very serious disorder that is often times fatal. The characteristic features of the disease are weakened skeletal muscles that tire with very little exertion. MG is an auto-immune disease associated with antibodies to the nAChR of the neuromuscular junction. Binding of the antibodies to the receptor results in receptor destruction as well as receptor cross-linking. In most patients with MG there is a 70%90% reduction in motor end plate nicotinic receptor number. Two major forms of MG exist, one in which the extraocular muscles are the ones primarily affected and in the other form there is a generalized skeletal muscle involvement. In the latter form of MG, the muscles of the diaphragm become affected resulting in respiratory failure which contributes to the mortality of MG. Treatment of MG involves numerous approaches including the use of acetylcholinesterase inhibitors. The use of these types of drugs allows for enhanced levels of ACh at the motor end plate during repeated muscle stimulation.

Once the molecules of neurotransmitter are releasedfrom a cell as the result of the firing of an action potential, they bind to specificreceptors on the surface of the postsynaptic cell. In all cases in which thesereceptors have been cloned and characterized in detail, it has been shown thatthere are numerous subtypes of receptor for any given neurotransmitter. As wellas being present on the surfaces of postsynaptic neurons, neurotransmitterreceptors are found on presynaptic neurons. Ingeneral, presynaptic neuron receptors act to inhibitfurther release of neurotransmitter.

The vast majority of neurotransmitter receptors belongto a class of proteins known as the G-protein coupled receptors, GPCRs. Go to the Signal Transduction page for more information on theses receptors. The GPCRs are also called serpentine receptors because they exhibit a characteristic transmembrane structure: that is, itspans the cell membrane, not once but seven times. The link betweenneurotransmitters and intracellular signaling is carried out by associationeither with the receptor-associated G-protein, withprotein kinases, or by the receptor itself in theform of a ligand-gated ion channel (for example, thenicotinic acetylcholine receptors). The receptors that are of the GPCR family are referred to as metabotropic receptors, whereas, the ligand-gated ion channel receptors are referred to as ionotropic receptors.

One additional characteristic of neurotransmitterreceptors is that they are subject to ligand-induced desensitization. Receptor desensitization refers to the phenomenon whereby upon prolonged exposure ligand results in uncoupling of the receptor from its signaling cascade. A common means of receptor desensitization involves receptor phosphorylation by receptor-specific kinases. Following phosphorylation of the receptor there is increased affinity for inhibitory molecules that uncouple the interaction of receptor with its associated G-protein. One major class of these desensitizing inhibitors are the arrestins. Arrestins were first identified in studies of -adrenergic receptor desensitization and so were called -arrestins.

synthesis pathway

synthesis pathway

synthesis pathway

ATP also binds to the ionotropic family of purinergic receptors (P2X) which consists of seven members (P2X1-P2X7); these receptors modulate synaptic transmission throughout the autonomic nervous systems of the CNS and PNS; in the periphery the P2X receptors activate contractile activity of various muscle types

Within the CNS glutamate is the main excitatory neurotransmitter. Neurons that respond to glutamate are referred to as glutamatergic neurons. Postsynaptic glutamatergic neurons possess three distinct types of ionotropic receptors that bind glutamate released from presynaptic neurons. These ionotropic receptors have been identified on the basis of their binding affinities for certain substrates and are, thus referred to as the the kainate, 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate(NMDA) receptors, and the delta () receptors. Each of these classes of glutamate receptor subunit form ligand-gated ion channels, thus the derivation of the term ionotropic. There are also multiple subtypes of each of these classes of ionotropic glutamate receptor subunits.

The AMPA receptor subunits are referred to as GluA1 (GluR1) through GluA4 (GluR4) and each is encoded by separate genes. Functional AMPA receptors consist of heterotetramers that are formed from dimers of GluA2 and dimers of either GluA1, GluA3, or GluA4. The GluA2 subunit of the receptor is responsible for regulating the permeability of the channel to calcium ions. The GluA2 mRNA is subject to RNA editing which alters the function of the calcium permeability character of the subunit. For details on the editing of the GluA2 mRNA go to the RNA Metabolism page. The AMPA receptors are found on most excitatory postsynaptic neurons where they mediate fast excitation. Indeed, AMPA receptors are responsible for the bulk of fast excitatory synaptic transmission throughout the CNS. The concept of fast synaptic transmission relates to the fact that the ion channel opens and closes quickly in response to ligand (e.g. glutamate) binding. The ion permeability of the AMPA receptors is controlled by the GluA2 subunit. AMPA receptors have low permeability to calcium ions even in the ligand-activated state and this is to prevent excitotoxicity in these neurons.

The NMDA receptor is generated from two separate subunit families. These subunit families are identified as GluN1 (also called NMDAR1) and GluN2. There are four GluN2 subunits (GluN2AGluN2D; also NMDAR2ANMDAR2D). The four different GluN2 subunits are encoded by distinct genes. Although there is a single gene encoding the GluN1 subunit, multiple isoforms of this subunit are generated through alternative splicing events. The functional NMDA receptor is composed of a heterotetramer with all forms containing the GluN1 subunit and one of the different GluN2 subunits. Unlike the other ionotropic glutamate receptors, the NMDA receptors are activated by simultaneous binding of glutamate and glycine. Glycine serves as a co-agonist and both amino acid neurotransmitters must bind in order for the receptor to be activated. Glycine binds to the GluN1 subunit while glutamate binds to the GluN2 subunit.Glutamate binding to NMDA receptors results in calcium influx into the postsynaptic cells leading to the activation of a number of signaling cascades. These signaling cascades can include activation of calcium/calmodulin-dependent kinase II (CaMKII) leading to phosphorylation of the GluA2 AMPA receptor subunit. This latter effect results in long-term potentiation (LTP).NMDA receptor activation also triggers PKC-dependent insertion of AMPA receptors into the synaptic membrane during LTP as well as activation of the kinases PI3K, AKT/PKB, and GSK3, each of which modulates LTP.

The kainate receptor subunits are known as GluK1 through GluK5 (formerly GluR5, GluR6, GluR7, KA1, and KA2). The GluK1GluK3 subunits can form hetero- and homomeric receptor complexes. In addition, alternative splicing of the GluK1 and GluK2 mRNAs results in at least five distinct subtypes (GluK1aGluK1c, GluK2a, GluK2b). Less is known about the physiological significance of the kainate receptors. One major role of the kainate receptors is in the regulation of synaptic plasticity. Another important function of the kainate receptors is in the regulation of the release of the inhibitory neurotransmitter GABA. This function of the kainate receptors is due to their presence on presynaptic GABAergic neurons.

The delta () glutamate receptors were identified as ionotropic glutamate receptors based upon amino acid sequence similarity to the other more well-characterized ionotropic glutamate receptors. However, these proteins do not form glutamate-gated functional ion channels either alone or in combination with any of the other ionotropic glutamate receptor proteins. Indeed, these proteins do not bind glutamate or any other excitatory amino acid receptor ligands. The GluD1 receptor (encoded by the GRID1 gene) is prominently expressed in inner ear hair cells and neurons of the hippocampus. The presentation of GluD1 in the inner ear indicates that it has a role in hearing. The GluD2 receptor (endcoded by the GRID2 gene) is expressed exclusively in the Purkinje cells of the cerebellum. GluD2 function is critical for the development of neuronal circuits and functions that includes long-term depression (LTD), learning and memory.

Within the CNS glutamatergic neurons are responsible for the mediation of many vital processes such as the encoding of information, the formation and retrieval of memories, spatial recognition and the maintenance of consciousness. Excessive excitation of glutamate receptors has been associated with the pathophysiology of hypoxic injury, hypoglycemia, stroke and epilepsy.

Glutamate can also bind to another class of receptor termed the metabotropic glutamate receptors (mGluRs; where the small m refers to metabotropic). There are eight known metabotropic glutamate receptors identified as mGluR1mGluR8. Unlike the ionotropic receptors, the mGluRs are members of the G-protein coupled receptor (GPCR) family. The mGluRs can be divided into three distinct subclasses based upon sequence similarities and receptor associated G-protein. Group I mGluRs include mGluR1 and mGluR5, both of which are coupled to Gq type G-proteins and upon activation trigger increased production of DAG and IP3. Group II is composed of mGluR2 and mGluR3. Group III is composed of mGluR4, mGluR6, mGluR7, and mGluR8. Both group II and III mGluRs activate an associated Gi type G-protein resulting in decreased production of cAMP. The mGluRs are primarily expressed on neurons and glial cells in close proximity to the synaptic cleft. Within the CNS, mGluRs modulate the neurotransmitter effects of glutamate as well as a variety of other neurotransmitters. In addition to the CNS, mGluRs have a widespread distribution in the periphery. Given their wide pattern of expression, diverse roles for mGluRs have been suggested. Some of these processes include control of hormone production in the adrenal gland and pancreas, regulation of mineralization in the developing cartilage, modulation of cytokine production by lymphocytes, directing the state of differentiation in embryonic stem cells, and modulation of secretory functions within the gastrointestinal tract.

Within the CNS there is an interaction between the cerebral blood flow, neurons, and the protective astrocytes that regulates the metabolism of glutamate, glutamine, and ammonia. This process is referred to as the glutamate-glutamine cycle and it is a critical metabolic process central to overall brain glutamate metabolism. Using presynaptic neurons as the starting point, the cycle begins with the release of glutamate from presynaptic secretory vesicles in response to the propagation of a nerve impulse along the axon. The release of glutamate is a Ca2+-dependent process that involves fusion of glutamate containing presynaptic vesicles with the neuronal membrane. Following release of the glutamate into the synapse it must be rapidly removed to prevent over excitation of the postsynaptic neurons. Synaptic glutamate is removed by three distinct process. It can be taken up into the postsynaptic cell, it can undergo reuptake into the presynaptic cell from which it was released or it can be taken up by a third non-neuronal cell, namely astrocytes. Postsynaptic neurons remove little glutamate from the synapse and although there is active reuptake into presynaptic neurons the latter process is less important than transport into astrocytes. The membrane potential of astrocytes is much lower than that of neuronal membranes and this favors the uptake of glutamate by the astrocyte. Glutamate uptake by astrocytes is mediated by Na+-independent and Na+-dependent systems. The Na+-dependent systems have high affinity for glutamate and are the predominantglutamate uptake mechanism in the central nervous system. There are two distinct astrocytic Na+-dependent glutamate transporters identified as EAAT1 (for Excitatory Amino Acid Transporter 1; also called GLAST) and EAAT2 (also called GLT-1).

Brain glutamate-glutamine cycle. Ammonium ion (NH4+) in the blood is taken up by astrocytes and incorporated into glutamate via glutamine synthetase. The glutamine then is transported to presynaptic neurons via SLC38A7 (also called sodium-coupled neutral amino acid transporter 7, SNAT7). Within the presynaptic neuron glutamate is formed from the glutamine via the action of glutaminase. The glutamate is packaged in secretory vesicles for release following activation of an action potential. Glutamate in the synaptic cleft can be taken up by astrocytes via the EAAT1 and EAAT2 transporters (excitatory amino acid transporters 1 and 2; also known as glial high affinity glutamte transporters). Within the astrocyte the glutamate is converted back to glutamine. Some of the astrocyte glutamine can be transported into the blood via the action of the transporter SLC38A3 (also called sodium-coupled neutral amino acid transporter 3, SNAT3).

Following uptake of glutamate, astrocytes have the ability to dispose of the amino acid via export into the blood though capillaries that contact the foot processes of the astrocytes. The problem with glutamate disposal via this mechanism is that it would eventually result in a net loss of carbon andnitrogen from the CNS. In fact, the outcome of astrocytic glutamate uptake is its conversion to glutamine. Glutamine thus serves as a "reservoir" for glutamate but in the form of a non-neuroactivecompound. Release of glutamine from astrocytes allows neurons to derive glutamate from this parent compound. Astrocytes readily convert glutamate to glutamine via the glutamine synthetase catalyzed reaction as this microsomal enzyme is abundant in these cells. Indeed, histochemical data demonstrate that the gliaare essentially the only cells of the CNS that carry out the glutamine synthetase reaction. The ammonia that is used togenerate glutamine is derived from either the blood or from metabolic processes occurring in the brain.

Like the uptake of glutamate by astrocytes, neuronal glutamine uptake proceeds via both Na+-dependent and Na+-independent mechanisms. The major glutamine transporter in both excitatory and inhibitory neurons is the system N neutral amino acid transporter SLC38A7 (also called SNAT7). The predominant metabolic fate of the glutamine taken up by neurons is hydrolysis to glutamate and ammonia via the action of the mitochondrial form of glutaminase encoded by the GLS2 gene. This form of glutaminase is referred to as phosphate-dependent glutaminase (PAG). The inorganic phosphate (Pi) necessary for this reaction is primarily derived from the hydrolysis of ATP and its function is to lowerthe KM of the enzyme for glutamine. During depolarization there is a sudden increase in energy consumption. The hydrolysis of ATP to ADP and Pi thus favors the concomitant hydrolysis of glutamine to glutamate via the resulting increased Pi. Because there is a need to replenish the ATP lost during neuronal depolarization, metabolic reactions that generate ATP must increase. It has been found that not all neuronal glutamate derived fromglutamine is utilized to replenish the neurotransmitter pool. A portion of the glutamate can be oxidized within the nerve cells following transamination. The principle transamination reaction involves aspartate aminotransferase (AST) and yields -ketoglutarate (2-oxoglutarate) which is a substrate in the TCA cycle. Glutamine, therefore, is not simply a precursor to neuronal glutamate but a potential fuel, which, like glucose, supports neuronal energy requirements.

Glutamate, released as a neurotransmitter, is taken up by astrocytes, converted to glutamine, released back to neurons where it is then converted back to glutamate represents the complete glutamate-glutamine cycle. The significance of this cycle to brain glutamate handling isthat it promotes several critical processes of CNS function. Glutamate is rapidly removed from the synapse by astrocytic uptake thereby preventing over-excitation of the postsynaptic neuron. Within the astrocyte glutamate is converted to glutamine which is, in effect, a non-neuroactive compound that can be transported back to the neurons. The uptake of glutamine by neurons provides a mechanism for the regeneration of glutamate which is augmented by the generation of Pi as a result of ATP consumption during depolarization. Since the neurons also need to regenerate the lost ATP, the glutamate can serve as a carbon skeleton for oxidation in the TCA cycle. Lastly, but significantly, the incorporation of ammonia into glutamate in the astrocyte serves as a mechanism to buffer brain ammonia.

Glycine, as an amino acid found in proteins, is critical to the functions of several different classes of protein, particularly those of the extracellular matrix. However, glycine as a free amino acid also functions as a highly important neurotransmitter within the central nervous system, CNS. Glycine and GABA are the major inhibitory neurotransmitters in the CNS, whereas, glutamate is the major excitatory neurotransmitter. In conjunction with glutamate, glycine can also function in an excitatory capacity as a co-agonist acting on the NMDA subtype of glutamate receptors (see section above). The receptors to which glycine binds were originally identifed by their sensitivity to the alkaloid strychnine. Strychnine-sensitive glycine receptors (GlyRs) mediate the synaptic inhibition exerted in response to glycine binding. Glycinergic synapses mediate fast inhibitory neurotransmission within the spinal cord, brainstem, and caudal brain. The effects of glycine exert control over a variety of motor and sensory functions, including vision and audition. The GlyRs are members of the ionotropic family of ligand-gated ion channels. The binding of glycine leads to the opening of the GlyR integral anion channel, and the resulting influx of Cl ions hyperpolarizes the postsynaptic cell, thereby inhibiting neuronal firing.

Cellular uptake of glycine, particularly within neurons in the central nervous system (CNS), is regulated by the presence of specific glycine transporters identified as GlyT. There are two subtypes of GlyT identified as GlyT1 and GlyT2. Both glycine transporters are members of the solute carrier family of membrane transporters. The GlyT1 protein is encoded by the SLC6A9 gene and the GlyT2 protein is encoded by the SLC6A5 gene. The tissue distribution and funciton of the two glycine transporters are distinct. GlyT1 is predominantly expressed in glutamatergic neurons where it functions in the regulation of glycine levels in the vicinity of the NMDA-type glutamate receptors. GlyT2 is predominantly expressed in glycinergic neurons where it functions to regulate inhibitory glycinergic neurotransmission by decreasing synaptic Gly concentrations afterpresynaptic release. A form of inherited hyperekplexia of presynaptic origin (HKPX3) results from mutations in the SLC6A5 (GlyT2) gene.

Impaired glutamatergic neurotransmission via the NMDA receptors has been associated with the symptoms of schizophrenia and the associated cognitive deficit. Pharmacologic inhibitors of GlyT1 have some utility to improve impaired NMDA receptor function in psychosis by increasingsynaptic glycine concentrations. These transport inhibitors function by increasing extrasynaptic Gly concentrations via inhibition of its neuronal or glial reuptakeprocesses. When used in combination with other antipsychotic medications, GlyT1 inhibitors have been shown to be capable of restoring disturbed glutamatergic-GABAergic-dopaminergicbalance in psychosis.

The receptors to which glycine binds (GlyRs) are members of the group I ligand-gated ion channel (LGIC) class of receptors. The LGIC receptors are members of the Cys loop receptor family that also includes the nicotinic acetylcholine receptors (nAChR), the serotonin type 3 receptor (5-HT3), and the GABAA receptors (GABAAR). The GlyRs are composed of three different proteins, two of which constitute the actual receptor and a third protein that serves a scaffolding function. The receptor subunits are referred to as GlyR and GlyR. These subunits are tightly bound to a cytosolic scaffolding protein identified as gephyrin. Gephyrin is tightly bound to the GlyR subunit. In addition to its role in GlyR function, gephryin (gene symbol: GPHN) functions to regulate the activity of the GABAA receptor and it is required for molybdenum cofactor biosynthesis. Functional GlyRs are heteropentameric proteins similar to the organization of the nAChRs found in skeletalmuscle. The typical subunit composition of the heteropentameric GlyR is (GlyR)2(GlyR)3.

Humans express four GlyR genes encoding subunits (GLRA1GLRA4) and a single GlyR gene encoding the subunit (GLRB). All GlyR subunits display high amino acid sequence identity and form functional homomericglycine-gated channels. The GlyR subunits possess criticaldeterminants of ligand binding. The GLRA1 gene is located on chromosome 5q32 and is composed of 10 exons that generate three alternatively spliced mRNAs. The GLRA2 gene is located on the X chromosome (Xp22.2) and is composed of 13 exons that generate four alternatively spliced mRNAs. Two of the splice variant GLRA2 mRNAs encode the same protein, thus, the four variant mRNAs generate three different GLRA2 proteins. The GLRA3 gene is located on chromosome 4q34.1 and is composed of 13 exons that generate two alternatively spliced mRNAs. The GLRA4 gene is located on the X chromosome (Xq22.2) on the other arm relative to the position of the GLRA2 gene. The GLRA4 gene is composed of 9 exons that generate two alternatively spliced mRNAs. Glycine receptors that contain the GlyR1 subunit represent the predominant form of the -subunit in adult glycine receptors. Several mutations in the GLRA1 gene have been shown to be associated with the startle disease known as hereditary hyperekplexia type 1, HKPX1. The hallmark symptoms of HKPX1 are an exaggerated startle response to auditory or tactile stimuli and, particularly in neonates, transient muscle rigidity referred to as stiff baby syndrome".

In addition to alternative splicing, the GLRA3 mRNA is subject to editing that results in the substitution of a Pro residue for a Leu residue at amino acid 185 in the extracellular domain. This version of the GlyR3 protein confers an increased agonist affinity to GlyR3-containing glycine receptors. The GlyR3-containing GlyRs are involved in the pathways of nociception (pain sensation) within the spinal cord. Specific spinal cord neurons (in laminae I and II) mediate pain sensation in response to the inflammatory mediator, prostaglandin E2 (PGE2). When PGE2 binds to its receptor in these neurons (the EP2 receptor), PKA is activated which then phosphorylates the GlyR3 protein in the glycine receptor resulting in down-regulation of glycine stimulated inhibitory circuits in these neurons. The analgesic effects of cannabinoids and endocannabinoids involves the modulation of GlyR3-containing glycine receptors. Thus, it is postulated that GlyR3 represents a potentially useful target for the pharmacologic intervention in chronic pain syndromes.

The GlyR gene is located on chromosome 4q31.3 and is composed of 12 exons that generate three alternatively spliced mRNAs that encode two distinct GlyR isoforms. Unlike the GlyR subunits which can form a functional glycine-gated ion channel, the GlyR protein cannot form a functional glycine receptor on its own. The role of the GlyR subunit is to regulate agonist binding and intracellular trafficking and synaptic clustering of post-synaptic GlyRs. Mutations in the GLRB gene are associated with another form of hyperekplexia identified as HKPX2.

Several amino acids have distinct excitatory orinhibitory effects upon the nervous system. The amino acid derivative, -aminobutyrate (GABA; also called4-aminobutyrate) is a major inhibitor of presynaptictransmission in the CNS, and also in the retina. Neurons thatsecrete GABA are termed GABAergic.

GABA cannot cross the blood-brain-barrier and as such must be synthesized within neurons in the CNS. The synthesis of GABA in the brain occurs via a metabolic pathway referred to as the GABA shunt. Glucose is the principal precursor for GABA production via its conversion to -ketoglutarate in the TCA cycle. Within the context of the GABA shunt the -ketoglutarate is transaminated to glutamate by GABA -oxoglutarate transaminase (GABA-T). Glutamic acid decarboxylase (GAD) catalyzes the decarboxylation of glutamic acid to form GABA. There are two GAD genes in humans identified as GAD1 and GAD2. The GAD isoforms produced by these two genes are identified as GAD67 (GAD1 gene: GAD67) and GAD65 (GAD2 gene: GAD65) which is reflective of their molecular weights. Both the GAD1 and GAD2 genes are expressed in the brain and GAD2 expression also occurs in the pancreas. The activity of GAD requires pyridoxal phosphate (PLP) as a cofactor. PLP is generated from the B6 vitamins (pyridoxine, pyridoxal, and pyridoxamine) through the action of pyridoxal kinase. Pyridoxal kinase itself requires zinc for activation. A deficiency in zinc or defects in pyridoxal kinase can lead to seizure disorders, particularly in seizure-prone pre-eclamptic patients (hypertensive condition in late pregnancy). The presence of anti-GAD antibodies (both anti-GAD65 and anti-GAD67) is astrong predictor of the future development of type 1 diabetes in high-risk populations.

GABA synthesis: The synthesis of GABA is a single step reaction involving the decarboxylation glutamate being catalyzed by glutamate decarboxylases (GAD).

GABA exerts its effects by binding to two distinctreceptor subtypes. The GABA-A (GABAA) receptors are members of the ionotropic receptors, specifically the Cys-loop subfamily of ligand-gated ion channels that includes the nicotinic ACh receptors (nAChR), glycine receptors (GlyR), and the 5-HT3 (serotonin) receptor. The GABA-B (GABAB) receptors belong to the class C family of metabotropic G-protein coupled receptors (GPCR). The GABA-A receptors are members of the ionotropic receptor family and are chloride channels that, in response to GABA binding, increase chloride influx into the GABAergic neuron. The GABA-B receptors are coupled to a G-protein that activates an associated potassium channel that when activated by GABA leads to potassium efflux from the cell. The anxiolytic drugs of the benzodiazepine family exert their soothing effects by potentiatingthe responses of GABA-A receptors to GABA binding.

Functional GABA-A receptors are generated by the combination of a wide array of different subunits. A total of 19 GABA-A receptor subunit genes have been identified in humans that code for (alpha), (beta), (gamma), (delta), (epsilon), (pi), (theta), and (rho). The overall diversity of GABA-A receptors is further increased as several of theses genes undergo alternative splicing. The complexity of the diverse array of molecular compositions of the GABA-A receptors has important functional and clinical consequences as they determine the properties and pharmacological modulations of a given receptor complex. In addition, zinc ions are known to regulate GABA-A receptor activity via inhibition of the receptor through an allosteric mechanism that is critically dependent on the receptor subunit composition. The GABRG3 (3 subunit gene) encoded protein is critical to this zinc-mediated regulation. Although the minimal requirement to produce a functional GABA-gated ion channel is the inclusion of both and subunits, the most common type in the brain is a heteropentameric complex composed of two subunits, two subunits, and a subunit (22). The GABA-A receptors bind two molecules of GABA and in the heteropentameric receptors this binding site is created by the interface between the and subunits.

The GABA-A subunits do not form heteromeric complexes with other GABA-A receptor subunits but only form homomeric receptor complexes. The GABA-A receptors were formerly referred to as the GABA-C receptors.

The anxiolytic/sedative effects of the barbiturates and benzodiazepines are exerted via their binding to subunits of the GABA-A receptors. Benzodiazepines bind to a site on the GABA-A receptor created by the association of the gamma () subunit and one of the the alpha () subunits. There are two distinct subtypes of benzodiazepine receptors termed BZ1 (BZ1) and BZ2 (BZ2). The BZ1 receptor is formed by the interaction of and 1 subunits, whereas the BZ2 receptors is formed by the interaction of the and 2, 3 or 5 subunits. The receptor for the barbiturates is the beta () subunit of the GABA-A receptor. When benzodiazepines bind to the GABA-A receptor they potentiate the actions of GABA and require the presence of GABA in order for activation of the ion channel. Barbiturates can induce GABA-A channel opening in the absence of GABA when administered at high dose and as a result they can be lethal due to the level of CNS suppression. The potential for lethal toxicity of a benzodiazepine requires an extremely large dose. This difference in toxicity between barbiturates and benzodiazepines is the major reason barbiturates are not often used clinically any longer.

Under physiological conditions the binding of GABA to any of the GABA-A receptors leads to membrane hyperpolarization and a reduction of action potential firing. However, studies have also demonstrated the GABA-A activation can result in membrane reversal potential that is close to, or even at a more depolarized potential than the resting membrane potential at a synapse. This results in a membrane depolarization referred to as shunting inhibition. Shunting inhibition is also called divisive inhibition and defines a form of post-synaptic potential inhibition. The term shunting is used because the synaptic conductance short-circuits currents that are generated at adjacent excitatory synapses. If a shunting inhibitory synapse is activated, the amplitude of subsequent excitatory postsynaptic potentials (EPSPs) is reduced. The major effect of GABA-A receptor activation is reduced dendritic excitatory glutamatergic responses as a consequence of a local increase in conductance across the plasma membrane. In addition to shunting inhibition, the polarity of GABA-A receptor-mediated responses can change during different physiological or pathological conditions. For example, GABA triggers excitation during the day and inhibition during the night within neural circuits of the suprachiasmatic nucleus. Also, the repeated activation of GABA-A receptors can lead to a switch from a hyperpolarizing to depolarizing direction and can, thus, enhance cell firing. The activation of GABA-A receptors results in both phasic inhibitory postsynaptic currents (IPSCs) and tonic currents. The GABA-A-induced tonic current result from GABA acting on extrasynaptic receptors composed of a different subunit composition and therefore, different pharmacological activity compared with the synaptic receptors.

GABA also acts on GABA-B receptors that are members of the GPCR family of receptors. There are two GABA-B receptors subunits identified as GABA-B1 (GABAB1) and GABA-B2 (GABAB2). These two subunits heterodimerize to form the functional receptor that can be found on both pre- and post-synaptic membranes. Neither receptor subunit is functional as a GABA receptor independently. The GABA-B receptors are coupled to G-proteins of the Gi type. The G-protein is linked to potassium channels (GIRK or Kir3) and activation of the G-protein results in increased conductance of the associated channel. GABA-B receptor activation on post-synaptic membranes generally leads to activation of the inwardly rectifying potassium channels which underlies the late phase of inhibitory postsynaptic potentials (IPSPs). Activation of pre-synaptic GABA-B receptors decreases neurotransmitter release by inhibiting voltage-activated Ca2+ channels of the N or P/Q types. Activation of GABA-B receptors also modulates the production of cAMP. This function leads to a wide range of actions on ion channels as well as other proteins that are targets of PKA. The cAMP modulation by GABA-B receptors effects modulation of both neuronal and synaptic functions.

The anxiolytic/sedative effects of the barbiturates and benzodiazepines are exerted via their binding to subunits of the GABA-A receptors. Benzodiazepines bind to a site on the GABA-A receptor created by the association of the gamma () subunit and one of the the alpha () subunits. There are two distinct subtypes of benzodiazepine receptors termed BZ1 (BZ1) and BZ2 (BZ2). The BZ1 receptor is formed by the interaction of and 1 subunits, whereas the BZ2 receptors is formed by the interaction of the and 2, 3 or 5 subunits. The receptor for the barbiturates is the beta () subunit of the GABA-A receptor. When benzodiazepines bind to the GABA-A receptor they potentiate the actions of GABA and require the presence of GABA in order for activation of the ion channel. Barbiturates can induce GABA-A channel opening in the absence of GABA when administered at high dose and as a result they can be lethal due to the level of CNS suppression. The potential for lethal toxicity of a benzodiazepine requires an extremely large dose. This difference in toxicity between barbiturates and benzodiazepines is the major reason barbiturates are not often used clinically any longer.The significance of the BZ1 receptor isoform is that it is solely involved in mediating the induction of sleep. This fact has led to the development of several classes of drug that specifically target this GABA-A receptor isoform, and more precisely, the site on the GABA-A complex that forms the BZ1 binding site. The non-benzodiazepine drug, zolpidem (Ambien), exerts its hypnotic sleep inducing effects due to near selective binding to the BZ1 site. Another non-benzodiazepine drug used for its hypnotic sleep inducing effect is eszopiclone (Lunesta). Although the precise mechanism of action of eszopiclone is not fully understood, it is believed to function similarly to zolpidem in binding to the BZ1 receptor site on GABA-A receptor isoforms.

Acetylcholine (ACh) is a simple molecule synthesizedfrom choline and acetyl-CoAthrough the action of choline acetyltransferase.Neurons that synthesize and release ACh are termed cholinergic neurons. When an actionpotential reaches the terminus of a presynapticneuron a voltage-gated calcium channel is opened. The influx of calcium ions,Ca2+, stimulates the exocytosis of presynaptic vesicles containing ACh,which is thereby released into the synaptic cleft. Once released, ACh must be removed rapidly in order to allow repolarization to take place; this step, hydrolysis, iscarried out by the enzyme, acetylcholinesterase (AChE). AChE is a highly active enzyme capable of hydrolyzing on the order of 25,000 molecules of ACh per second. The released choline is then taken back up by the presynaptic neuron where it can once again serve as a substrate for ACh synthesis via choline acetyltransferase.

Two different mammalian AChE isoforms are produced from the single ACHE gene (chromosome 7q22.1) in humans via alternative splicing and post-translational modification. These two AChE isoforms are termed T (tail) and H (hydrophobic). The T form (AChET, also known as the hydrophilic form) is the predominant enzyme in the brain and at the neuromuscular junction. The H form (AChEH) is the principal enzyme form found in erythroid cells. The AChEH isoform is anchored to red blood cell membranes via a GPI-linkage and this form constitutes the Yt blood group antigen.

Two main classes of ACh receptors have been identified on the basis of theirresponsiveness to the toadstool alkaloid muscarine and to nicotine, respectively. The muscarinic receptors (mAChRs) and the nicotinicreceptors (nAChRs). The muscarinic receptors are G-protein coupled receptors (GPCR) and are also referred to as metabotropic receptors. The nicotinic receptors are ligand-gated ion channels which are also referred to as ionotropic receptors. Both receptor classes are abundant in the human brain.

The are five subtypes of muscarinic receptors, identified as M1M5, that are classified based upon pharmacological activity. The M1, M3, and M5 muscarinic receptors are coupled to the Gq type G-proteins that activate PLC. The M2 and M4 receptors are coupled to Gi type G-proteins that inhibit adenylate cyclase. Muscarinic receptor desensitization occurs in response to phosphorylation of the receptors by kinases that are members of the G-protein coupled receptor kinase (GRK) family. For example the M2 receptor is phosphorylated by GRK2 (originally called -adrenergic receptor kinase-1, ARK1). More information on the GRK family can be found in the Signal Transduction page.

Nicotinic receptors are divided into those found at neuromuscular junctions and those found at neuronal synapses. The nicotinic receptors are composed of five types of subunits which are found in different combinations in different types of nicotinic receptors. There are 16 known nAChR subunit genes in the human genome that encode the alpha (17, 9, and 10), beta (14), delta (), epsilon (), and gamma () subunits. The alpha subunit genes are designated CHRNA1CHRNA7, CHRNA9, and CHRNA10. The beta genes are CHRNB14, while the delta, gamma, and epsilon genes are CHRND, CHRNG, and CHRNE, respectively. Regardless of subunit composition or cellular location, all of the nAChRs are pentameric receptors. All of the nAChRs are divided into two broad categories: neuromuscular-type and neuronal-type. Regardless of type, nAChRs that contain the 4 and 2 subunits are the highest affinity receptors.

There are two major types of neuromuscular nicotinic receptors; one is composed of 1, 1, , and subunits (referred to as the embryonic form) while the other is composed of 1, 1, , and (referred to as the adult form). There are five types of neuronal receptors, with one of the latter type also found in epithelial tissues. The neuronal nAChRs are only composed of various and subunits making up the pentameric receptor. For example, the ganglion nAChR is comprised of an (3)2(4)3 pentameric arrangement.

The activation of nicotinic acetylcholine receptors by the binding of ACh leads to an influx of Na+ into the cell and an efflux of K+, resulting in a depolarization of the postsynaptic neuron and the initiation of a new action potential. Desensitization of the nAChRs occurs as a result of phosphorylation by either PKA or PKC.

Numerous compounds have been identified that act aseither agonists or antagonists of cholinergic neurons. The principal action ofcholinergic agonists is the excitation or inhibition of autonomic effector cells that are innervated by postganglionicparasympathetic neurons and as such are referred to asparasympathomimetic agents. The cholinergic agonists include choline esters (such as AChitself) as well as protein- or alkaloid-based compounds. Several naturallyoccurring compounds have been shown to affect cholinergic neurons,either positively or negatively.

The responses of cholinergic neurons can also beenhanced by administration of cholinesterase (ChE)inhibitors. ChE inhibitors have been used ascomponents of nerve gases but also have significant medical application in thetreatment of disorders such as glaucoma and myasthenia gravis as well as interminating the effects of neuromuscular blocking agents such as atropine.

Pharmacological intervention in the functions of acetylcholine is effected by either of two routes. In the direct-acting class there are the acetylcholine mimicking drugs (cholinomimetics) and in the indirect-acting class are the acetylcholinesterase inhibitors. There are numerous cholinomimetic drugs which includes methacholine, carbachol, and bethanechol as prominent examples. Methacholine exerts its effects through the muscarinic acetylcholine receptors and is used primarily in the bronchial challenge test used to diagnose hyperactivity in the bronchial tree as it typical in asthma. Carbachol functions primarily by activating nicotinic acetylcholine receptors and can exert systemic effects in the gastrointestinal system and in the bladder. However, it is used primarily as a locally administered drug in the treatment of glaucoma. Bethanechol is a muscarinic acetylcholine receptor agonis used primarily in the treatment of urinary retention following anesthesia and in diabetic neuropathy.

Acetylcholinesterase (AChE) inhibitors are used to increase the effective level and action of acetylcholine acting at both muscarinic and nicotinic acetylcholine receptors. Aceythcholinesterase inhibitors that are used pharmacologically are principally of the reversible (competitive and noncompetitive) type. Irreversible AChE inhibitors exert toxic effects such as the effects of the toxic organophosphate pesticides and nerve agents. The reversible AChE inhibitors, such as donepezil, rivastigmine and galantamine, are commonly used in the treatment neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD). These reversible inhibitors are also used to treat the neuromuscular disorder, myasthenia gravis, that results from autoimmune destruction of nicotinic acetylcholine receptors (nAChR). Reversible AChE inhibitors are also used as antidotes in the treatment of organophosphate pesticide intoxication. Although these AChE inhibitors are used to reduce the symptoms associated with AD they do not exert their effects in the long term (being effective for only 12-24 months) and they have no effects on the rate of cognitive decline in AD. The carbamates (derived from carbamic acid: NH2COOH) represent a large class of compounds, many of which are reversible AChE inhibitors (e.g. rivastigmine). Although reversible, the carbamates can exert acute toxic effects that are similar to those of the irreversible organophosphates. Indeed, several carbamate compounds are used as pesticides and parasiticides in the veterinary field. Clinically the carbamates are used in the treatment of myasthenia gravis, glaucoma, and neurodegenerative disorders such as AD and PD, similarly to donepezil and galantamine. Although the irreversible AChE inhibitors are quite toxic and have been used as deadly nerve agents (e.g. VX) and as insecticides, they do have pharmacologic utility. The drug echothiophate (phospholine) is administered locally in the treatment of glaucoma and metrifonate is used in the treatment of AD and PD.

As described above, the neurotransmitters and receptors of the parasympathetic nervous system are those of the cholinergic family. The principal neurotransmitter is acetylcholine (ACh) and the receptors are the muscarinic acetylcholine receptors M2 and M3. For example, the primary vascular response to ACh binding to M3 receptors on endothelial cells is the activation of nitric oxide synthase (NOS) and the production of nitric oxide (NO). However, it is important to note that the endothelial M3 receptor is not innervated by cholinergic nerve fibers, but responds to the binding of circulating ACh. Production of NO results in relaxation of the smooth muscle cells leading to vasodilation. Nicotinic ACh receptors are located postsynaptically in all autonomic ganglia and at the neuromuscular junction (NMJ). At the NMJ, nicotinic receptors function as the excitatory receptor for the postsynaptic cell.

As pointed out in the introduction to this page, neurotransmission within the sympathetic and parasympathetic ganglia involves the release of ACh from preganglionic efferent nerves. Once released, the ACh then binds to nicotinic receptors in the membrane of the cell bodies of the postganglionic efferent nerves. Ganglionic blockers (primarily nicotinic ACh receptor antagonists) are drugs that function by inhibiting autonomic activity via interference with the transmission of nerve impulses within autonomic ganglia. Therefore, ganglionic blockers reduce sympathetic outflow. With respect to cardiac tissue, ganglionic blockade results in decreased cardiac output due to both decreased chronotropic (heart rate) and inotropic (contraction strength) activity. Ganglionic blockers also lead to reduced sympathetic output to the vasculature resulting in decreased sympathetic vascular tone. This latter effect causes vasodilation and reduced systemic vascular resistance resulting in decreased arterial pressure. It is important to note that parasympathetic nerve transmission (outflow) is also reduced by ganglionic blocking drugs. For this reason, as well as the development of more highly selective drugs for the treatment of hypertension, ganglionic blockers (e.g. mecamylamine and hexamethonium) are not commonly used any longer in the treatment of hypertension.

The principal catecholaminesare norepinephrine, epinephrineand dopamine. These compounds are formed from the amino acid tyrosine. Tyrosine is produced, primarily, in the liver from phenylalanine through theaction of phenylalanine hydroxylase. The tyrosine isthen transported to catecholamine-secreting neurons where a series of reactionsconvert it to dopamine, to norepinephrine and finallyto epinephrine (see also SpecializedProducts of Amino Acids). Within the substantia nigra locus of the brain, and someother regions of the brain, synthesis proceeds only to dopamine. Within the locus coeruleus region of the brain the end product of the pathway is norepinephrine. The presence of high concentrations of tyrosine in the locus coeruleus and the substantia nigra leads to increased melanin synthesis which confers on these brain regions a dark bluish coloration observable in brain sections. Indeed, these brain regions are so-called due to the dark bluish-black pigmentation. The Latin term, substantia nigra, means "black substance". The Latin word coeruleus means "dark blue, blue, or blue-green". Within adrenal medullary chromaffin cells, tyrosine is converted to norepinephrine and epinephrine.

Synthesis of the catecholamines from tyrosine. Tyrosine is converted to each of the three catecholamines through a series of four reactions. The tissue from which the neurotransmitter/hormone is derived expresses a specific set, or all, of these enzymes such that only dopamine (substantia nigra) is the result, or only norepinephrine (locus coeruleus), or both norepinephrine and epinephrine (adrenal medulla). DOPA decarboxylase (also known as aromatic L-amino acid decarboxylase) is encoded by the DDC gene. Dopamine -hydroxylase is a critical vitamin C (ascorbate) and copper (Cu2+)-dependent enzyme.

Once synthesized, dopamine, norepinephrine and epinephrine are packaged in granulated vesicles for secretion in response to the appropriate nerve impulse. Within these vesicles, norepinephrine and epinephrine are bound to ATP and a protein called chromogranin A. Norepinephrine is the principal neurotransmitter of sympathetic postganglionic nerves. Both norepinephrine and epinephrine are stored in synaptic knobs of neurons that secrete it, however, epinephrine is not a mediator at postganglionic sympathetic nerve impulses. The major location, within the brain, for norepinephrine synthesis is the locus coeruleus of the brainstem. The major brain region for the synthesis of dopamine is the substantia nigra which is located below the posterior hypothalamus and next to the ventral tegmetal area. Outside the brain, the major site of norepinephrine and epinephrine synthesis is in adrenal medullary chromaffin cells. Outside the brain, dopamine is synthesized in several tissues including the gastrointestinal system where its actions reduce gastrointestinal motility, the pancreas where its actions inhibit insulin synthesis, and in the kidneys where its actions increase sodium excretion and urinary output.

Catecholamines exhibit peripheral nervous system excitatory and inhibitory effects as well as actions in the CNS such as respiratory stimulation and an increase in psychomotor activity. The excitatory effects are exerted upon smooth muscle cells of the vessels that supply blood to the skin and mucous membranes. Cardiac function is also subject to excitatory effects, which lead to an increase in heart rate and in the force of contraction. Inhibitory effects, by contrast, are exerted upon smooth muscle cells in the wall of the gut, the bronchial tree of the lungs, and the vessels that supply blood to skeletal muscle. In addition to their effects as neurotransmitters, norepinephrine and epinephrine can influence the rate ofmetabolism. This influence works both by modulating endocrine function such asinsulin secretion and by increasing the rate of glycogenolysisand fatty acid mobilization.

The primary effects of the catecholamines are exerted as neurotransmitters upon their stimulated release from presynaptic nerve terminals in the appropriate target organ. However, release of the catecholamines from adrenal medullary cells to the systemic circulation allow them to function as hormones as well. Regardless of their site of release, the catecholamines exert their effects by binding to receptors of the G-protein coupled receptor (GPCR) family. The catecholamines are also known as adrenergic neurotransmitters and the neurons that secrete them are referred to as adrenergic neurons. Norepinephrine-secreting neurons are specifically termed noradrenergic neurons. Some of the norepinephrine released from presynaptic noradrenergic neurons is recycled in the presynaptic neuron by a reuptake mechanism similar to that responsible for regulating the CNS actions of serotonin.

The actions of norepinephrine and epinephrine are exerted upon binding to and activating the adrenergic receptors of which there are nine distinct forms. As indicated, the adrenergic receptors are all members of the GPCR family. There are two distinct types of adrenergic receptor identified as the (alpha) and (beta) receptors. In addition, there are two functionally distinct classes of adrenergic receptor identified as the 1 and 2 forms. Within each -adrenergic receptor type there are several variants encoded by distinct genes as well as additional isoforms that result from alternative mRNA splicing. The 1 receptors consist of the 1A, 1B, and 1D receptors. The 1 receptors are coupled to Gq-type G-proteins that activate PLC resulting in increases in IP3 and DAG release from membrane PIP2. The 2 receptors consist the 2A, 2B, and 2C receptors. The 2 receptors are coupled to Gi-type G-proteins that inhibit the activation of adenylate cyclase and therefore, receptor activation results in reduced levels of cAMP and consequently reduced levels of active PKA. The adrenergic receptors are composed of three types: 1, 2, and 3 each of which couple to Gs-type G-proteins resulting in activation of adenylate cyclase and increases in cAMP with concomitant activation of PKA. However, the 2 receptor can switch from Gs to Gi/o signaling following phosphorylation of the receptor by PKA.

Dopamine binds to dopamineric receptors identified as D-type receptors and there are five receptors identified as D1, D2, D3, D4, and D5. All five dopamine receptors belong the the G-protein coupled receptor (GPCR) family. The D1 and D5 dopamine receptors are coupled to the activation of Gs-type G-proteins and, therefore, receptor activation results in activation of adenylate cyclase. The D2, D3, and D4 dopamine receptors are coupled to Gi-type G-proteins and, therefore, receptor activation results in the inhibition of adenylate cyclase. The D1 and D5 receptors constitute members of the D1-like receptor family. The D2, D3, and D4 receptors constitute members of the D2-like receptor family.

With respect to the sympathetic nervous system (see above), the principal neurotransmitters are norepinephrine and epinephrine and the receptors are 1, 1, and 2. Alpha-adrenergic receptors of the sympathetic nervous system play important roles in cardiac and vascular function. The presence of the 1 receptor in arteries causes them to constrict upon binding epinephrine or norepinephrine. This effect results in increased blood pressure and increased blood flow returning to the heart. Significantly, however, is the fact that the blood vessels in skeletal muscles lack 1 receptors so that they can remain open to utilize the increased blood pumped by the heart, particularly in response to stress.

When considering the effects of various adrenergic receptor agonist and antagonist effects within the vasculature it is important to understand that the contractile characteristics and the mechanisms that cause contraction of cardiac myocytes and vascular smooth muscle (VSM) are very distinct. The contractile properties of cardiac myocytes are fast and of extremely short duration. In contrast, VSM undergoes slow, sustained, tonic contractions. While both cardiac muscle and VSM contain actin and myosin, VSM do not express the regulatory troponin complex as do striated muscle cells such as cardiac myocytes. An additional difference between VSM and cardiac myocytes relates to the structural arrangement of actin and myosin. In heart muscle cells these proteins are organized into distinct bands, whereas, in VSM they are not. Although organized differently, the contractile proteins of VSM are indeed highly organized in order to allow for maintaining tonic contractions and reducing vascular diameter.

Contraction of VSM is initiated by by several distinct phenomena including mechanical, electrical, and chemical stimuli. Mechanical contraction refers to the passive stretching of VSM from the cell itself and is therefore termed a myogenic response. Electrical stimulation of VSM contraction involves depolarization of the membrane, most often as a result of the opening of voltage gated calcium channels (L-type calcium channels) leading to increased intracellular calcium concentrations. When discussing chemical stimuli, that initiate contraction in VSM, these signals are hormones and neurotransmitters such as epinephrine and norepinephrine, angiotensin II, vasopressin (anti-diuretic hormone, ADH), endothelin-1, and thromboxane A2 (TXA2). Each of these molecules binds to specific receptors on the VSM cell or to receptors on the endothelial cells adjacent to the VSM. The consequences of receptor activation are VSM contraction. Although each of these receptor-mediated VSM contraction processes are different, they converge at the point of increased intracellular calcium concentration.

Increases in free intracellular calcium result from either increased calcium influx into the VSM or via the release of sarcoplasmic reticulum (SR) stored calcium. Within the VSM cell, free calcium binds to the regulatory protein, calmodulin. Calcium-calmodulin activates myosin light chain kinase (MLCK) which then phosphorylates myosin light chains. Phosphorylation of myosin light chains induces the formation of cross-bridges between the myosin heads and the actin filaments leading to smooth muscle contraction.Conversely, relaxation of VSM cells occurs in response to reduced levels of myosin light chain phosphorylation. Adrenergic receptor stimulation by epinephrine or norepinephrine involves G-protein-coupled signal transduction pathways that impinge upon levels of the PKA activating molecule, cAMP. Since 1 receptors are coupled to the activation of Gq proteins there is a resultant increase in release of intracellular calcium via the action of the second messenger IP3 binding to SR membrane receptors. The consequences of the released calcium are, therefore, VSM contraction. Norepinephrine is the major activator of 1 receptors. Norepinephrine also activates 2 receptors which are Gi coupled receptors. The resultant inhibition of cAMP production due to the inhibition of adenylate cyclase leads to increased MLCK activity. The effects, therefore, of norepinephrine at 1 and 2 receptors are the same but elicited via different signaling pathways. On the other hand, epinephrine activates 2 receptors which are coupled to Gs proteins which activate adenylate cyclase resulting in increased cAMP concentrations. In most cells an increase in cAMP leads to an increase in the activity of the kinase, PKA. Although it would seem counterintuitive for this pathway to be activated under conditions where VSM relaxation was needed, the increased cAMP levels induced by VSM 2 receptor activation result in inhibition of MLCK, thereby reducing myosin light chain phosphorylation. In addition, activated PKA phosphorylates a membrane potassium channel (KATP) in VSM resulting in hyperpolarization of the cell preventing the Ca2+ influx that is required for contraction. The net effect of both of these 2 receptor-medicated events is VSM relaxation.

Activation of the 1 receptor in the heart results in an increase in both the inotropic (heart rate) and the chronotropic (strength of contraction) activity of the heart muscle. Pharmacologic antagonism of the 1 receptor in the heart, such as with metoprolol (or any other of this drug class; identifiable by the olol' ending), results in decreasing heart rate and contractility. The overall effect is a decrease in blood pressure. This is the basis for the use of beta blocker drugs in the treatment of hypertension and to decrease the chance of a dysrhythmia after a heart attack. The 2 receptors are prevalent in the smooth muscle cells of the bronchioles of the lungs and arteries of skeletal muscle. Activation of the 2 receptors in bronchioles causes them to dilate which allows more oxygenated air to enter the lungs. Simultaneously, activation of 2 receptors in the arteries of skeletal muscle causes them to dilate to allow increased blood flow into this tissue. Both of these receptor-mediated activities allow for an enhanced response to stress such as is typical of the fight-or-flight response. It is important to note that norepinephrine also binds weakly to 2 receptors which results in vasodilation as for the case of epinephrine. This phenomenon is most noticeable pharmacologically when 1 blockers such as prazosin (drugs in this class all end in 'osin') are utilized. Under normal physiological conditions this vasodilator effect of norepinephrine is overwhelmed by 1 receptor-mediated vasoconstriction. Equally important is the fact that, although epinephrine binds with highest affinity to VSM 2 receptors to induce vasodilation, at high concentrations it will bind to 1 and 2 receptors which can override 2 receptor effects leading to vasoconstriction.

Epinephrine and norepinephrineare catabolized to inactive compounds through thesequential actions of catecholamine-O-methyltransferase(COMT) and monoamine oxidase (MAO). Compounds thatinhibit the action of MAO have been shown to have beneficial effects in thetreatment of clinical depression, even when tricyclicantidepressants are ineffective. The utility of MAO inhibitors was discoveredserendipitously when patients treated for tuberculosis with isoniazidshowed signs of an improvement in mood; isoniazid wassubsequently found to work by inhibiting MAO.

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Biochemistry of Neurotransmitters and Nerve Transmission