Propagated action potentials carry information through axons over long distances, but they do not transfer electrical impulses directly to other neurons, glands, or muscle cells. Communication between most nerve cells is accomplished via neurotransmitter molecules released at synapses.
Synthesis. Acetylcholine is synthesized from acetyl coenzyme A (CoA) and choline by the enzyme choline acetyltransferase in the presynaptic terminal. The uptake of choline is the rate-limiting step.
Pantothenic acid (vitamin B5) is a precursor of CoA. CoA participates in fatty acid synthesis and oxidation, as well as the oxidation of pyruvate in the citric acid cycle. A molecule of CoA that has an acetyl group is referred to as acetyl CoA. Acetate, which is derived from acetyl CoA, combines with choline to form the neurotransmitter a cetylcholine.
Degradation. Breakdown is rapid via acetylcholinesterase to produce acetate and choline. Acetylcholinesterase is located on neuronal membranes, muscle cell membranes, and red blood cells. Pseudocholinesterases (nonspecific) and butyrylcholinesterases, which are more widely distributed, can also hydrolyze acetylcholine.
Release. Acetylcholine is the neurotransmitter released from the following neurons (see also page 35 and Fig. 4.1):
– Pre- and postganglionic parasympathetic neurons
– Preganglionic sympathetic neurons
– Postganglionic sympathetic neurons that innervate sweat glands
– Motoneurons at the neuromuscular junction
Synthesis. Norepinephrine is synthesized from the precursor amino acid tyrosine by hydroxylation to dihydroxyphenylalanine (dopa) in the postganglionic neuron. Dopa is decarboxylated to dopamine, which is oxidized to norepinephrine and packaged in vesicles.
Degradation. Termination of action is primarily by reuptake (60–90%) into nerve terminals. Secondary degradation is by monoamine oxidase (MAO) and catechol O-methyltransferase (COMT).
Monoamine oxidase inhibitors
Monoamine oxidase inhibitors (MAOIs, e.g., isocarboxazid and phenelzine) inhibit both forms of the enzyme monoamine oxidase (MAO-A and MAO-B). In doing so, they prevent the degradation of norepinephrine, epinephrine, and dopamine. These drugs are used in the treatment of depression when tricyclic antidepressants are in effective. It takes 2 to 3 weeks for the desired effects of these drugs to occur.
Hypertensive crisis with monoamine oxidase inhibitors
Hypertensive crisis may occur within hours of ingestion of tyramine-containing foods, including cheese, certain meats (liver and fermented or cured meats), cured or pickled fish, overripe fruits and vegetables, Chianti wine, and some beers. Hypertensive crisis is characterized by headache, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever or cold, clammy skin), photophobia, tachycardia or bradycardia, constricting chest pain, and dilated pupils. Potentially fatal intracranial bleeding may result from this crisis. Patients should avoid tyramine-containing foods while taking MAOIs and for 2 weeks after treatment with MAOIs is discontinued to avoid precipitating this condition, but if it does occur, then treatment is with intravenous phentolamine.
Release. Norepinephrine is the main neurotransmitter released from postganglionic sympathetic neurons. It is also released in small quantities from the adrenal medulla along with epinephrine.
Synthesis. Epinephrine is produced from norepinephrine in the adrenal medulla via the enzyme phenylethanolamine N-methyltransferase.
Degradation. Epinephrine is degraded by MAO and COMT.
Release. Epinephrine is released from the adrenal medulla along with some norepinephrine.
Synthesis. Dopamine is a precursor in the formation of both norepinephrine and epinephrine.
Degradation. Dopamine is degraded by MAO and COMT.
Release. Dopamine acts as a neurotransmitter in the central nervous system (CNS), especially in the extrapyramidal motor system.
Synthesis. Glutamate is synthesized from glucose via glutamine.
Degradation. Glutamate is converted back to glutamine, and its action is terminated by reuptake into cells in the CNS.
Release. Glutamate is the principal excitatory amino acid neurotransmitter in the CNS.
Synthesis. Glucose is the principal in vivo source of gamma-aminobutyric acid (GABA). There is a GABA “shunt” of the Krebs cycle that results in the conversion of glutamate into GABA by the action of the enzyme glutamate decarboxylase.
Degradation. GABA is converted back to glutamate, then to glutamine. Its action is terminated by reuptake into cells in the CNS.
Release. GABA is the principal inhibitory amino acid neurotransmitter in the CNS.
Synthesis. Serotonin (5-hydroxytryptamine [5-HT]) is synthesized from tryptophan by tryptophan hydroxylase.
Degradation. Serotonin is degraded by MAO.
Release. Serotonin acts as a neurotransmitter in the CNS.
Carcinoid tumors are neuroendocrine tumors of the gastrointestinal (GI) tract, urogenital tract, or pulmonary bronchioles. They can contain and secrete numerous autocoids, including prostaglandins and serotonin, causing symptoms such as flushing and diarrhea. Cardiac disease due to fibrosis of the endocardium and valves, along with asthma-like symptoms, are also common. Flushing may be precipitated by stress, alcohol, certain foods, or drugs, particularly serotonin-specific reuptake inhibitors (SSRIs), so these should be avoided. Heart failure, wheezing, and diarrhea are treated, respectively, with diuretics, a bronchodilator, and an antidiarrheal agent, such as loperamide or diphenoxylate. If patients remain symptomatic, serotonin receptor antagonists, antihistamines, and somatostatin analogues are the drugs of choice. 5-HT3 receptor antagonists (ondansetron, tropisetron, dolasetron, granisetron, palonosetron, ramosetron, alosetron, and cilansetron) can control diarrhea and nausea and occasionally ameliorate the flushing. A combination of histamine H1 and H2 receptor antagonists (diphenhydramine and cimetidine or ranitidine) may control flushing in patients with upper GI or pulmonary carcinoids. Synthetic analogues of somatostatin (octreotide and lanreotide) are the most widely used agents to control the symptoms of patients with carcinoid syndrome.
Synthesis. Glycine is the simplest amino acid.
Degradation. Glycine is broken down by glycine dehydrogenase.
Release. Glycine is released by the inhibitory interneurons in the spinal cord that are activated by group Ia muscle afferents (see page 65). It acts by increasing Cl− conductance in the postsynaptic membrane, hyperpolarizing it, and thus preventing action potential generation.
Synthesis. Histamine is synthesized from histidine by histidine decarboxylase.
Degradation. Histamine is degraded by MAO.
Release. Histamine acts as a neurotransmitter in the CNS.
Synthesis. Nitric oxide (NO) is not stored in vesicles. It is synthesized as required in the pre-synaptic terminal from arginine by the enzyme NO synthase.
Degradation. NO has a half-life of only a few seconds.
Release. NO acts as an inhibitory neurotransmitter in the CNS, GI tract, and blood vessels.
Table 2.1 provides examples that are predominantly excitatory or inhibitory.
2.2 Synaptic Transmission
An action potential depolarizes the presynaptic terminal cell membrane, causing membrane Ca2+ channels to open and Ca2+ influx into the presynaptic terminal. This Ca2+ influx then stimulates the release of neurotransmitters from storage vesicles into the synaptic cleft (Fig. 2.1).
Fig. 2.1 Synaptic signal transmission.
An action potential (AP) arriving at the presynaptic membrane (1) causes voltage-gated Ca2+ channels to open (2). This increase in intracellular [Ca2+] triggers the release of neurotransmitters from their storage vesicles into the synaptic cleft (3). Neurotransmitter molecules then diffuse across the synaptic cleft (4) and bind with inotropic or metabotropic receptors on the postsynaptic membrane. Inotropic receptors are ligand-gated ion channels. Ligand (in this case, neurotransmitter) binding (5) causes the inflow of ions into the cell, resulting in either depolarization (inflow of cations) or hyperpolarization (inflow of anions). (6) Ligand binding to metabotropic receptors activates G proteins, which transduce a cellular response via second messenger molecules.
The neurotransmitters released diffuse across the synaptic cleft and bind to ligand-gated channels on the postsynaptic cell membrane, causing a change in conductance of ions.
– Excitatory postsynaptic potentials (EPSPs) are produced when excitatory neurotransmitters open Na+ channels, resulting in depolarization of the postsynaptic membrane. K+ channels also open, but the combined effect still depolarizes.
– Inhibitory postsynaptic potentials (IPSPs) are produced when inhibitory neurotransmitters open Cl− channels, resulting in stabilization or hyperpolarization of the postsynaptic membrane.
An action potential is generated when the summated EPSPs and IPSPs bring the membrane to threshold. The neurotransmitter dissociates from the receptor and is removed from the synapse via enzymatic degradation, reuptake, or diffusion.
Summation of Postsynaptic Potentials. Postsynaptic neurons summate postsynaptic potentials spatially and temporally to integrate the total excitatory and inhibitory flow (Fig. 2.2).
– Spatial summation is the addition of synaptic depolarizations originating from various regions of the neuron.
– Temporal summation is the synchronicity of depolarizations, with additional depolarizations occurring before previous ones decay.
2.3 Neuromuscular Transmission
The neuromuscular junction is the synapse between motoneurons and skeletal muscle fibers.
An action potential in the motoneuron depolarizes the membrane, causing membrane Ca2+ channels to open and Ca2+ influx into the presynaptic terminal. This Ca2+ influx then stimulates the release of acetylcholine from their storage vesicles into the synaptic cleft.
Acetylcholine diffuses across the synaptic cleft and interacts with nicotinic receptors on the postsynaptic membrane (motor end plate). The acetylcholine receptor is a Na+ and K+ ion channel. The binding of acetylcholine to this receptor causes an increased conductance of Na+ and K+ at the end plate, creating an end plate potential (EPP).
Botulinum toxin is a neurotoxin produced by the anaerobic bacteria Clostridium botulinum. It prevents the release of acetylcholine at the neuromuscular junction, thereby causing paralysis of skeletal muscles. It is highly potent, and if respiratory muscles are paralyzed, it is lethal. In its purified form (Botox), this paralysis of muscles is temporary (3–4 months) and is used cosmetically to soften the appearance of wrinkles. It is also used therapeutically in the treatment of many conditions, including cervical dystonia (a neuromuscular disorder of the head and neck), severe hyperhydriasis (excessive sweating), achalasia (failure of the lower esophageal sphincter [LES] to relax), and migraine.
Myasthenia gravis is an autoimmune disease in which there are too few functioning acetylcholine receptors at the neuromuscular junction. P atients with this condition often present in young adulthood with easy fatiguability of muscles, which may progress to permanent muscle weakness. Treatment involves using neostigmine or similar agents to prolong the action of released acetylcholine.
Fig. 2.2 Summation of postsynaptic potentials: (A) spatial summation of stimuli; (B) temporal summation of stimuli.
Multiple presynaptic APs causing excitatory postsynaptic potentials (EPSPs) are summed to stimulate an action potential in the axon hillock of the postsynaptic neuron. The EPSPs may be summated spatially or temporally. In spatial summation (A), multiple APs arrive at the axon hillock simultaneously, and although none of them could generate an AP individually, their summated effect results in an AP. In temporal summation (B), presynaptic APs occurring close together in time generate a large summed EPSP.
End Plate Potentials. End plate potentials (EPPs) result from synchronous release of hundreds of vesicles of acetylcholine from the presynaptic terminal of the motoneuron, causing depolarization of the postsynaptic membrane (Fig. 2.3). This depolarization results in the influx of Na+ through the postsynaptic membrane of the end plate. An action potential is generated when the summated EPPs bring the membrane region surrounding the end plate to threshold, causing the muscle to generate its own action potential. Miniature end plate potentials (MEPPs) occur upon spontaneous release of a single vesicle filled with ~10,000 molecules of neurotransmitter. They depolarize the postsynaptic membrane only 1 mV.
Fig. 2.3 Motor end plate.
Motor end plates are the contact between motor axon terminals and skeletal muscles fibers. The acetylcholine (ACh) vesicles release their contents into the synaptic cleft, where ACh binds with receptors on the sarcolemma. At the neuromuscular junction, motoneurons interface with muscle fibers. APs that travel along motoneurons will stimulate the muscle fibers to contract if the depolarization caused by the release of ACh from the presynaptic terminal reaches threshold and generates an AP at the end plate.