Neurotransmitter

a neurotransmitter (C7H17NO3) released at autonomic and central nervous system synapses and neuromuscular junctions.

From: Reference Module in Neuroscience and Biobehavioral Psychology, 2017

Chapters and Articles

Neurotransmitters

J.R. Cooper, in International Encyclopedia of the Social & Behavioral Sciences, 2001

2 Biogenic Amines

Four neurotransmitters come under the chemical classification of biogenic amines. These are epinephrine, norepinephrine, dopamine, and serotonin. Although epinephrine is the transmitter in frogs, in mammals its role has been supplanted by norepinephrine. Epinephrine's function in the mammalian brain is still unclear and may be limited to a hormonal role.

Starting with tyrosine, the catecholamines (norepinephrine and dopamine) are synthesized in a cascade of reactions beginning with the rate-limiting enzyme, tyrosine hydroxylase. Figure 2 depicts the enzymes and cofactors involved. The catecholamines are catabolized by two enzymatic pathways (Fig. 3) involving monamine oxidase, a neuronal mitochondrial enzyme, and catechol-o-methyltransferase, a cytoplasmic enzyme, found primarily in the kidney and the liver. However, as noted earlier, when norepinephrine and dopamine are released into the synapse, their activity is terminated by reuptake into the presynaptic terminal rather than by enzymatic catabolism. The reuptake is inhibited by a number of antidepressant drugs.

Figure 2. Synthesis of the catecholamine transmitters. The synthesizing enzymes are shown to the right of each arrow, and the enzyme cofactors to the left.

Figure 3. Catabolism of norepinephrine follows multiple pathways depending upon whether the process begins with deamination (left pathway) or O-methylation (right pathway). Aldehyde products of MOA (DHPGA and MHPGA) may be reduced to DHPG and MHPG, or oxidized to DHMA and VMA.

Noradrenergic neurons arise from the locus coeruleus, the lateral tegmental system, and a dorsal medullary group and innervate virtually all areas of the brain and spinal cord. Central effects of noradrenaline stimulation are not clear but appear to involve behavioral attention and reactivity.

Peripherally where noradrenaline is released from postganglionic sympathetic neurons of the autonomic nervous system, the major effects are to regulate blood pressure, relax bronchi, and relieve nasal congestion. These effects are mediated by the major receptors, α and β, each again with multiple subtypes.

At one time dopamine was thought to be just an intermediate in the conversion of tyrosine to noradrenaline. It is now clear, however, that dopamine is a major player in the CNS with its implication in Parkinson's disease and in schizophrenia. Dopamine cells originate in the substantia nigra, ventral tegmental area, caudal thalamus, periventricular hypothalamus, and olfactory bulb. Dopaminergic terminals are found in the basal ganglia, the nucleus acumbens, the olfactory tubercle, the amygdala, and the frontal cortex. The nigrostriatal pathway is particularly important since its degeneration is involved in Parkinson's disease. Initially, dopamine receptors were classified as D1 or D2. Currently the subtypes consist of D1 through D5 with the possibility of a D6. All the receptors are coupled to G proteins as their second messenger. Arising from the observation that a correlation existed between therapeutic doses of antipsychotic drugs and inhibition of binding of dopamine receptor antagonists, the D2 receptor has been fingered in the pathophysiology of schizophrenia. The atypical neuroleptic drug clozapine, however, exhibits a greater affinity for the D4 receptor, dopaminergic transmission in the nucleus accumbens, involving both D1 and D2 receptors, is believed to be involved in the reward activity of abused drugs such as cocaine. The catabolism of dopamine is shown in Fig. 4.

Figure 4. Catabolism of dopamine by (left pathway) oxidative deamination by MAO or (right pathway) O-methylation. DOPAC and 3-MT are indicators of intraneuronal catabolism and of catabolism of released DA, respectively.

The last of the biogenic amine neurotransmitters to be discussed is serotonin (5-hydroxytryptamine). Its synthesis and its catabolism are depicted in Figs. 5 and 6. In addition to its presence in the CNS, serotonin is found in the GI tract and in blood platelets. It is also localized in the pineal gland where it serves as a precursor to the hormone melatonin. Serotinergic neurons innervate the limbic system, the neostriatum, cerebral and cerebellar cortex and the thalamus. Currently, 18 serotonin receptor subtypes have been identified. Most are G-protein linked except for the 5-HT3 receptor which is ligand gated. Hallucinogen drugs have been shown to act on the 5-HT2A receptors. Serotonin receptor antagonists that are relatively specific have been used to treat migraine headaches, body-weight regulation and obsessive–compulsive disorders.

Figure 5. Serotonin (5-HT) synthesized from the amino acid tryptophan in two steps, catalyzed by the enzymes tryptophan hydroxylase and aromatic L-amino acid decarboxylase. The cofactor for each reaction is shown.

Figure 6. Serotonin is initially catabolized by the mitochondrial enzyme monoamine oxidase to yield the intermediate 5-hydroxyindoleacetaldehyde, which is rapidly converted to 5-hydroxyindoleacitic acid by the enzyme aldehyde dehydrogenase.

Decarboxylation of the amino acid histidine results in the formation of histamine, a still questionable neurotransmitter. This amine does not qualify as a transmitter according to the rigid definitions outlined earlier, since no evidence exists for either its release on stimulation of a neuronal tract, nor is there a rapid reuptake mechanism or enzymatic catabolism to terminate its activity. Histaminergic neurons are located almost exclusively in the ventral posterior hypothalamus and project throughout the entire CNS. Three histamine receptors have been described, H1, H2 and H3. Antagonists of H1 are the well-known antihistamine drugs which exhibit a sedative action. H2 antagonists are used to block gastric acid secretion. H3 receptors are autoreceptors which, when activated, inhibit the release of histamine.

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Neurotransmitters

James H. Schwartz, in Encyclopedia of the Human Brain, 2002

V.A.1. Acetylcholine (ACh)

ACh is formed in a single enzymatic step. The enzyme, choline acetyltransferase, catalyzes the esterification of choline by acetyl-CoA.

The transferase is specific to cholinergic neurons and is not expressed in any other cell type. (The term cholinergic is used to denote a cell that releases ACh as a neurotransmitter. Similarly, glutaminergic, dopaminergic, and serotonergic indicate that a neuron releases glutamate, dopamine, or serotonin, respectively. If a cell responds to ACh, that cell is called cholinoceptive, a term used infrequently for the other neurotransmitters; e.g., “dopaminoceptive” is unusual.) The formation of ACh is limited by the supply of choline. Choline is not made in nervous tissue, but must be obtained through the cerebrospinal fluid from dietary sources or recaptured from the synaptic cleft from the ACh released and hydrolyzed by the enzyme acetylcholinesterase (see later discussion).

There are two general classes of acetylcholine receptors (AChR): nicotinic, responding to the alkaloid nicotine, and muscarinic, responding to the mushroom poison, muscarine. ACh is excitatory at the neuromuscular junction, where it binds to postsynaptic nicotinic AChRs. As we saw with Loewi's experiment, it is an inhibitory (parasympathetic) transmitter to the heart through muscarinic AChRs. In the periphery, ACh is also the transmitter for all preganglionic neurons of the autonomic nervous system. In the brain, there are many cholinergic systems, for example, cholinergic neurons in the nucleus basalis have widespread projections to the cerebral cortex.

Nicotinic AChRs are ionotropic, meaning that, when they bind ACh, they open up to pass ions from the extracellular space into the postsynaptic neuron. Muscarinic AChRs are metabotropic. These receptors activate various second messenger pathways to produce biochemical changes within the postsynaptic neuron. Thus, as with other neurotransmitters, ACh can excite or inhibit depending on the postsynaptic receptor.

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Basic Elements of Signal Transduction Pathways Involved in Chemical Neurotransmission

Claudia González-Espinosa, Fabiola Guzmán-Mejía, in Identification of Neural Markers Accompanying Memory, 2014

Neurotransmitters

Neurotransmitters and neuromodulators are the molecules responsible for the transmission of information on chemical synapses. For a molecule to be considered as a neurotransmitter (i) must be stored in vesicles together with the enzymes responsible for its synthesis; (ii) must be released in response to an increase in intracellular Ca2+; and (iii) the exogenous administration of the neurotransmitter should elicit the same response as it were endogenously produced.

Neurotransmitters can be classified into two groups: (i) classic, such as amino acid derivatives and (ii) neuropeptides. The main neurotransmitters associated with learning and memory, together with its receptors and signaling systems, are given in Table 8.1.

Table 8.1. Main Neurotransmitters Associated with Learning and Memory, its Receptors and Canonical Signaling Pathways

NeurotransmitterReceptorsReceptor SubtypesCoupling
AcetylcholineGCPRM1 y M3Gq
Ion ChannelsM2 y M4Gi/o
M5Gq
nAChRNa+
Adrenaline/noradrenalineGCPRΒGs
α1Gq
α2Gi/o
DopamineGCPRD1 (D1y D5)Gs
D2(D2S, D2L, D3, D4)Gi/o
SerotoninGCPR5HT1 y 5HT5Gi/o
Ion channels5HT2Gq
5HT4, 5HT6 y 5HT7Gs
5HT3Na+ y K+
HistamineGCPRH1Gq
H2Gs
H3 y H4Gi/o
GlutamateGCPRmGluR1 y 5Gq
Ion channelsmGluR2, 3,4,6,7,8Gi/o
AMPANa+, K+, Ca2+
Kainate
NMDA
GABAGCPRGABA BGi/o
Ion channelsGABA A and CCl
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Neurotransmitter Transporters

K. Erreger, ... C. Saunders, in Encyclopedia of Biological Chemistry (Second Edition), 2013

Abstract

Neurotransmitters are chemical messengers by which neurons communicate with each other. High affinity uptake of neurotransmitters is mediated by transporter proteins and is the most common mechanism for the termination of neurotransmitter signaling. Transporters clear neurotransmitters not only to control the timing of neurochemical communication, but also to recapture transmitter molecules for later reuse. In addition to their obvious and critical role in neurotransmitter homeostasis, transporters are also important targets for therapeutic drugs as well as drugs of abuse and known neurotoxins. Here, we summarize the mechanism of transporter function, how transporter protein structure defines the functional properties of transporters, the cellular signals, and determinants that regulate transporters, and how disease states are related to neurotransmitter transporter dysfunction.

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Cells, Synapses, and Neurotransmitters

Joseph Feher, in Quantitative Human Physiology (Second Edition), 2012

Removal or Destruction of the Neurotransmitter Shuts Off the Neurotransmitter Signal

Neurotransmitters bind to their receptor by mass action. This principle states that the rate of binding is proportional to the concentration of free ligand (neurotransmitter) and free receptor, and the rate of unbinding or desorption is proportional to the concentration of bound ligand. This is stated succinctly in the equations

[4.2.1]L+PkonLPLPkoffL+P

Thus, the occupancy of the receptor P with the neurotransmitter L will decrease only when the free ligand concentration falls. Lowering the concentration of free neurotransmitter in the synaptic gap, therefore, will shut off the continued effect on the post-synaptic cell. As shown in Figure 4.2.7, there are three general ways to achieve this end: (1) destruction of the neurotransmitter by degradative enzymes; (2) diffusion of the neurotransmitter away from the post-synaptic receptors; and (3) reuptake of the neurotransmitter either by the pre-synaptic terminal or by other cells.

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Neurobiology and Endocrinology for Animal Behaviorists

Michael D. Breed, Janice Moore, in Animal Behavior, 2012

Neurotransmitters Shuttle Information from Neuron to Neuron

Neurotransmitters are the messengers of the nervous system. They are relatively small molecules that carry information across synapses from a nerve cell to its neighboring cells and are a critical part of the internal machinery controlling animal behavior. Generally speaking, the neurotransmitter is held in membrane-bound vesicles near the synapse. The nerve cell with these vesicles is the presynaptic cell. When stimulated, the vesicles merge with the cell membrane of the presynaptic cell, and the neurotransmitter is released into the synapse, or “synaptic space.” The neurotransmitter molecules cross the synaptic space and match with receptor molecules in the membrane of the postsynaptic cell, causing depolarization in that membrane and continuing the transmission of the impulse. These receptors are critically important; for each neurotransmitter there are several receptor molecule types, guaranteeing a transmitter-specific message. Each neurotransmitter has many different functions in the nervous system, and the receptor type involved in regulating a behavior often tells us more about the behavior than the identity of the neurotransmitter might tell us. The most common neurotransmitter is acetylcholine, which often is the messenger between axons and muscles as well. Other common neurotransmitters are octopamine, serotonin, and dopamine; they usually function in the central nervous system. All of these neurotransmitters are found in both vertebrates and invertebrates.

Key Term

Neurotransmitters are small molecules that carry messages among axons and between the nervous system and other tissues and organs.

Key Term

Acetylcholine is a neurotransmitter that acts, in many animals, at synapses between nerves and muscles.

For this system to work, the neurotransmitter must be removed from the synapse after the signal is no longer needed. This happens by either cleaving the neurotransmitter to inactivate it or by re-uptake of the neurotransmitter into the presynaptic cell. For instance, a specialized enzyme called acetylcholine esterase breaks down acetylcholine in the synapse. The components can then be recycled. In contrast, serotonin is taken up directly by the presynaptic cell (see Figure 2.3).

Figure 2.3. The chemical structures of three common neurotransmitters: (A) serotonin, sometimes called 5-hydroxy tryptamine, (B) dopamine, and (C) acetylcholine. These molecules share small size, the presence of a nitrogen molecule, and polarity, that is, having a chemical charge difference across the compound. Collectively such compounds are sometimes referred to as biogenic amines. Their small size allows them to be easily transported across cell membranes, but their polarity reduces unintended diffusion across non-polar cellular membranes. Insecticides like malathion, which is commonly used in mosquito control, are acetylcholine esterase inhibitors. This means the insecticide prevents the enzyme that breaks down acetylcholine in the synapses from acting. The resulting accumulation of acetylcholine results in uncoordinated firing of nerves.

Note

Insecticides like malathion, which is commonly used in mosquito control, are acetylcholine esterase inhibitors. This means the insecticide prevents the enzyme that breaks down acetylcholine in the synapses from acting. The resulting accumulation of acetylcholine results in uncoordinated firing of nerves and leads to death of the insect.

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Neurotransmitters and Their Life Cycle☆

Javier Cuevas, in Reference Module in Biomedical Sciences, 2019

Abstract

Neurotransmitters are the chemical messengers that allow electrical signals from neurons to be transmitted to the postsynaptic neuron or effector target. A substance is generally considered a neurotransmitter if it is synthesized in the neuron, is found in the presynaptic terminus and released to have an effect in the postsynaptic cell, is mimicked by exogenous application to the postsynaptic cell, and has a specific mechanism for termination of its action. Various types of molecules, ranging from simple gases, such as nitric oxide (NO), to complex peptides, such as pituitary adenylate cyclase-activating peptide, satisfy these criteria. Most small-molecule neurotransmitters, such as acetylcholine and dopamine, are synthesized in the cytoplasm of the nerve terminal and transported into vesicles; a variety of substrates and biosynthetic enzymes are involved in the synthesis of small-molecule neurotransmitters. Only 12 small-molecule neurotransmitters have been identified, but over 100 neuroactive peptides have been identified. Unlike small-molecule neurotransmitters, neuropeptides are encoded by specific genes and are synthesized from protein precursors formed in the cell body. The emerging understanding of atypical neurotransmitters such as the gases NO and CO, lipid mediators, and the phenomena of gliotransmitter action and exosomal transmission is constantly revising the understanding of what constitutes a “neurotransmitter.”

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Psychiatric Neuroscience: Incorporating Pathophysiology into Clinical Case Formulation

Eric M. Morrow MD, PhD, ... Joseph T. Coyle MD, in Massachusetts General Hospital Comprehensive Clinical Psychiatry, 2008

Neurotransmitters

Neurotransmitters are defined by four essential characteristics (Figure 40-7 and Table 40-4): they are synthesized within the presynaptic neuron; they are released with depolarization from the presynaptic neuron to exert a discrete action on the postsynaptic neuron; their action on the postsynaptic neuron can be replicated by administering the transmitter exogenously (as a drug); and their action in the synaptic cleft is terminated by a specific mechanism.3 However, they otherwise differ considerably in structure, distribution, and function. Their chemical makeup (including small molecules [such as amino acids, biogenic amines, and nitrous oxide] as well as larger peptides [such as opioids and substance P]) varies substantially. Certain neurotransmitters are found ubiquitously throughout the cortex, whereas others act in more select locations. Moreover, while certain neurotransmitters are always excitatory (e.g., glutamate) or inhibitory (e.g., GABA in the adult brain), others can exert variable downstream effects based on where they are located and to which receptors they bind.

Nearly 100 neurotransmitters have been identified within the mammalian brain. However, we will focus on several well-characterized neurotransmitter systems with major relevance to neuropsychiatric phenomena (Table 40-5). Each of these neurotransmitters plays an important role in normal brain function; thus, abnormal activity in any of these neurotransmitter systems may contribute to neuropsychiatric dysfunction. We will consider the normal “life cycle” for each neurotransmitter system—including synthesis, synaptic release, receptor binding, neurotransmitter degradation, postsynaptic signaling through ion channels or second messengers, and activity-dependent changes in gene expression and subsequent neuronal activity (see Table 40-4). We will focus particularly on the various points in this cycle that are amenable to pharmacological intervention.

For example, consider the hypothetical synapse in Figure 40-8. Suppose a particular psychiatric symptom was related to abnormally high synaptic concentrations of a specific neurotransmitter. The diversity of biochemical steps involved in the neurotransmitter cycle provides many targets for pharmacological intervention5: one could inhibit neurotransmitter synthesis; interfere with neurotransmitter transport, vesicle formation, or release; block postsynaptic receptor effects; or increase the clearance rate from the synapse by degradation or transport. We will revisit this model as we consider each of the neurotransmitter systems and their relation to normal and abnormal brain function below.

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Neurotransmitter Receptors

Richard Knapp, ... Henry I. Yamamura, in Encyclopedia of the Neurological Sciences, 2003

Neurotransmitters

Neurotransmitters are chemical compounds released by neurons after depolarization that act on other neurons to produce a response (Fig. 3). The response produced by a neurotransmitter is mediated by a neurotransmitter receptor capable of recognizing it. Neurotransmitters are the principal means by which neurons transfer information to each other. Characteristics of a neurotransmitter include its synthesis in the neuron, concentration in membrane-enclosed vesicles at presynaptic terminals, release by neuron terminal depolarization, induced activity at the postsynaptic terminal as a consequence of receptor binding, and removal from the synapse to terminate this effect. The defining characteristics of neurotransmitters have become less stringent due to evidence of some neurotransmitter release at nonsynaptic sites and because of the properties of unusual neurotransmitter-like molecules such as nitric oxide.

Figure 3. The synthesis, storage, action, and termination of norepinephrine, a representative brain neurotransmitter. (A) Norepinephrine is synthesized in the nerve cell and packaged into vesicles. In preparation for release, these vesicles are transported to the nerve terminal. (B) Upon arrival of an action potential at the axon terminal and the resultant calcium entry, vesicles fuse with the nerve terminal membrane, thereby releasing their contents into the synapse. (C) Released neurotransmitter diffuses across the synaptic cleft and can interact with postsynaptic receptor targets to cause excitatory or inhibitory postsynaptic potentials and/or stimulate second messenger systems. Termination of the response is accomplished by removing free neurotransmitter from the synapse. (D) Simple diffusion can carry the neurotransmitter out of the synapse, or (E) enzymes [e.g., monoamineoxidase (MAO)] can degrade or chemically modify the neurotransmitter, rendering it incapable of further action. (F) Finally, reuptake of neurotransmitter back into the presynaptic neuron or into surrounding cells can terminate the signal as well as recycle some of the neurotransmitter. (See color plate 39.)

There are many different neurotransmitter molecules (Fig. 4). They can be categorized as small molecules and much larger neuropeptides. The smallest neurotransmitter may be nitric oxide, with a molecular weight of 30, whereas the neurotransmitter peptide endorphin is composed of 30 amino acids and has a molecular weight of more than 3000—a 100-fold difference in size. Most neurotransmitters are localized to discrete parts of the nervous system, but three (adenosine, glutamate, and glycine) are present in every cell of an organism. Some neurotransmitters, including acetylcholine, norepinephrine, serotonin, and dopamine, can produce excitatory or inhibitory effects depending on the receptors on which they act. The diversity of structural and functional properties makes it difficult to categorize neurotransmitters.

Figure 4. Examples of neurotransmitters representing the major families. (A) Norepinephrine, (B) dopamine, (C) serotonin, (D) acetylcholine, (E) glutamic acid, and (F) γ-aminobutyric acid (GABA) are small molecule neurotransmitters, where glutamic acid is also an amino acid neurotransmitter. (G) Nitric oxide is an unusual neurotransmitter in that it is an unstable soluble gas. (H) β-Endorphin is a much larger peptide neurotransmitter.

The functional properties of a neurotransmitter differ in several important ways beyond the response produced at the postsynaptic site. Differences include their site of production within the neuron, the kinetics or time course of their response, and the method of removal from the synapse after release.

Small molecule transmitters, such as acetylcholine, epinephrine, norepinephrine, serotonin, and dopamine, are produced at the presynaptic terminal by local enzymes. All these except acetylcholine are produced from amino acid precursors, such as tyrosine (epinephrine, norepinephrine, and dopamine) or tryptophan (serotonin). Acetylcholine is produced by the acetylation of choline, a common nutrient. Peptide neurotransmitters such as enkephalin, dynorphin, cholecystokinin, and substance P are produced by the cleavage of much larger protein precursors primarily in the cell body of the neuron near its nucleus. The active neuropeptide products are packaged in secretory granules and then transported to their sites of release. One consequence of this difference between small and large neurotransmitters is that under conditions of high activity the neuropeptide supply at the presynaptic terminal can be exhausted.

The response kinetics for neurotransmitters differs depending on the type of receptor on which they act. Neurotransmitters acting on ion channel receptors such as glutamate (excitatory) and GABA (inhibitory) produce very fast responses (milliseconds). Glutamate and GABA also act on another class of receptors referred to as metabotropic or G protein-coupled receptors. These responses are much slower and can last for seconds to hours. The response mediated by an ion channel receptor results from the flow of ions (sodium, potassium, chloride, or calcium) that occurs when the transmitter opens the channel. Responses mediated by G protein-coupled receptors occur more slowly because they result from the activation of an extended series of enzymes.

There are two principal mechanisms by which neurotransmitters are removed from the synaptic space. The majority of neurotransmitters, including all neuropeptides and many small neurotransmitters, either diffuse away from their site of release or are destroyed by enzymes present on cell membrane surfaces. Acetylcholine is a classic example because it is very rapidly destroyed by acetylcholine esterase, which hydrolyzes the ester bond between the acetic acid and choline components of the neurotransmitter. Neuropeptides are degraded into their constituent amino acids by protease enzymes. Some small molecule neurotransmitters (e.g., norepinephrine, dopamine, and serotonin) are recaptured by the presynaptic terminal through a process called reuptake. Reuptake provides a means of recycling the transmitter so that high levels of neurotransmission can be maintained.

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Neurotransmission and the peripheral autonomic nervous system

Derek G. Waller BSc (HONS), DM, MBBS (HONS), FRCP, Anthony P. Sampson MA, PhD, FHEA, FBPhS, in Medical Pharmacology and Therapeutics (Fifth Edition), 2018

Principles of Neurotransmission

Action potentials (APs) passing along neuronal axons signal to other neurons or nonneuronal cells (e.g. smooth muscle cells). Signals are transferred by the release of chemical neurotransmitters from the presynaptic endings of the neuron, which diffuse across the synaptic cleft and stimulate the receiving (postsynaptic) cells via receptor proteins (Fig. 4.1). The binding of the transmitter to the receptors may instruct the receiving cells to increase or reduce their activity.

Neurotransmitters can be either synthesised within the presynaptic axon terminal (e.g. noradrenaline) or transported from the cell body to the synaptic region (e.g. peptides). The neurotransmitter is taken up from the cytosol by specific vesicular transporters within the nerve ending and stored within membrane vesicles. The release of the neurotransmitter can be ‘fine-tuned’ by axo-axonic connections and by presynaptic receptors (discussed later). A generalised scheme for neurotransmission is as follows (see Fig. 4.1):

1.

The cell body (or soma) responds to an appropriate stimulus by generating an AP.

2.

The AP is conducted along the axon by the opening of voltage-gated Na+ channels and the influx of Na+; when the AP reaches the presynaptic nerve terminal, it results in an influx of Ca2+ through voltage-dependent channels.

3.

Ca2+-dependent processes result in fusion of neurotransmitter-containing vesicles with the presynaptic membrane and the release of stored neurotransmitter into the synaptic cleft.

4.

The released neurotransmitter binds to the appropriate receptors in the postsynaptic membranes and generates biochemical changes in the recipient cells; these may be functional changes (e.g. smooth muscle contraction) or excitation or inhibition of another neuron (e.g. transmission of the AP to postsynaptic nerve fibres).

5.

The released neurotransmitter may also stimulate autoreceptors in the presynaptic membranes, and thereby modulate the further release of the neurotransmitter.

6.

The transmitter is degraded by enzymes or taken back into the presynaptic neuron for reuse.

Neurons may release a single transmitter, but often more than one transmitter is released; there are many examples of co-transmission, which are described later in this book.

Presynaptic Receptors and Modulation of Transmitter Release

An important characteristic of neurons is the presence of presynaptic receptors (see Fig. 4.1 and Table 4.1). Presynaptic receptors may increase or, more typically, decrease the release of the neurotransmitter, and are described as facilitatory and inhibitory, respectively. Inhibition of transmitter release is usually achieved by limiting Ca2+ entry through voltage-gated ion channels into the neuron. There are two functional categories of presynaptic receptors:

autoreceptors respond to neurotransmitter released from the neurons upon which the receptor sits,

heteroceptors respond to neurotransmitters released from other neurons, usually by axo-axonal synapses (see Fig. 4.1).

The first recognition of a clinically important presynaptic receptor came with the discovery that the antihypertensive agent clonidine lowers blood pressure via stimulation of presynaptic α2-adrenoceptors, with subsequent inhibition of the release of vasoconstricting noradrenaline. Presynaptic receptors (see Table 4.1) are increasingly recognised as playing important roles in the clinical effects produced by many drugs.

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