Acetylcholine is the transmitter at the neuromuscular junction, in autonomic ganglia, and in postganglionic parasympathetic nerve-target organ junctions and some postganglionic sympathetic nerve-target junctions. In fact, acetylcholine is the transmitter released by all neurons that exit the CNS (cranial nerves, motor neurons, and preganglionic neurons). Acetylcholine is also found in the basal forebrain complex (septal nuclei and nucleus basalis), which projects to the hippocampus and neocortex, and the pontomesencephalic cholinergic complex, which projects to the dorsal thalamus and forebrain (Figure 1). These systems may be involved in regulation of sleep-wake states, learning, and memory.
Fig1. Four diffusely connected systems of central neuromodulators. A) Noradrenergic neurons in the locus coeruleus innervate the spinal cord, cerebellum, several nuclei of the hypothalamus, thalamus, basal telencephalon, and neocortex. B) Serotonergic neurons in the raphe nuclei project to the hypothalamus, limbic system, neocortex, cerebellum, and spinal cord. C) Dopaminergic neurons in the substantia nigra project to the striatum and those in the ventral tegmental area of the midbrain project to the prefrontal cortex of the limbic system. D) Cholinergic neurons in the basal forebrain complex project to the hippocampus and the neocortex and those in the pontomesencephalotegmental cholinergic complex project to the dorsal thalamus and the forebrain. (Reproduced with permission from Boron WF, Boulpaep EL: Medical Physiology. St. Louis, MO: Elsevier; 2005.)
Acetylcholine is largely enclosed in small, clear synaptic vesicles in high concentration in the terminals of cholinergic neurons. It is synthesized in the nerve terminal from choline and acetyl-CoA by the enzyme choline acetyltransferase (ChAT) (Figure 2 and Figure3). Choline used in the synthesis of acetylcholine is transported from the extracellular space into the nerve terminal via a Na+-dependent choline transporter (CHT). Following its synthesis, acetylcholine is transported from the cytoplasm into vesicles by a vesicle associated transporter (VAT). Acetylcholine is released when a nerve impulse triggers the influx of Ca2+ into the nerve terminal.
Fig2. Biosynthesis of some common small-molecule neurotransmitters. A) Glutamate is synthesized in the Krebs cycle by the conversion of α-ketoglutarate to the amino acid via the enzyme γ-aminobutyric acid transferase (GABA-T) or in nerve terminals by the hydrolysis of glutamine by the enzyme glutaminase. GABA is synthesized by the conversion of glutamate by the enzyme glutamic acid decarboxylase (GAD). B) Acetylcholine is synthesized in the cytoplasm of a nerve terminal from acetyl-Co-A and choline by the enzyme choline acetyltransferase. C) Serotonin is synthesized from the amino acid tryptophan in a two-step process: the enzymatic hydroxylation of tryptophan to 5-hydroxytryptophan and the enzymatic decarboxylation of this intermediate to form 5-hydroxytryptamine (also called serotonin). D) Catecholamines are synthesized from the amino acid tyrosine by a multi-step process. Tyrosine is oxidized to dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydroxylase in the cytoplasm of the neuron; DOPA is then decarboxylated to dopamine. In dopaminergic neurons, the process stops there. In noradrenergic neurons, the dopamine is transported into synaptic vesicles where it is converted to norepinephrine by dopamine-β hydroxylase. In neurons that also contain the enzyme phenylethanolamine-N-methyltransferase, norepinephrine is converted to epinephrine.
Fig3. Biochemical events at a cholinergic synapse. Choline is transported into the presynaptic nerve terminal by a Na+ dependent choline transporter (CHT), which can be blocked by the drug hemicholinium. Acetylcholine (ACh) is synthesized from choline and acetyl Co-A (AcCoA) by the enzyme choline acetyltransferase (ChAT) in the cytoplasm. ACh is then transported from the cytoplasm into vesicles by the vesicle-associated transporter (VAT) along with peptides (P) and adenosine triphosphate (ATP). This step can be blocked by the drug vesamicol. ACh is released from the nerve terminal when voltage-sensitive Ca2+ channels open, allowing an influx of Ca2+, which leads to fusion of vesicles with the surface membrane and expulsion of ACh and co-transmitters into the synaptic cleft. This process involves synaptosome associated proteins (SNAPs) and vesicle-associated membrane proteins (VAMPs) and can be prevented by the drug botulinum toxin. The released ACh can act on muscarinic G-protein—coupled receptors on the postsynaptic target (eg, smooth muscle) or on nicotinic ionotropic receptors in autonomic ganglia or the endplate of skeletal muscle (not shown). In the synaptic junction, ACh is readily metabolized by the enzyme acetylcholinesterase. Autoreceptors and heteroreceptors on the presynaptic nerve ending modulate neurotransmitter release.
Acetylcholine must be rapidly removed from the syn apse if repolarization is to occur. The removal occurs by way of hydrolysis of acetylcholine to choline and acetate, a reaction catalyzed by the enzyme acetylcholinesterase in the synaptic cleft. This enzyme is also called true or specific cholinesterase. Its greatest affinity is for acetylcholine, but it also hydrolyzes other choline esters. Acetylcholinesterase molecules are clustered in the postsynaptic membrane of cholinergic synapses. Hydrolysis of acetylcholine by this enzyme is rapid enough to explain the observed changes in Na+ conductance and electrical activity during synaptic transmission. There are a variety of cholinesterases in the body that are not specific for acetylcholine. One found in plasma is capable of hydrolyzing acetylcholine but has different properties from acetylcholinesterase. It is called pseudocholinesterase. The plasma moiety is partly under endocrine control and is affected by variations in liver function.
