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CHEMICAL NEUROTRANSMISSION


CHEMICAL NEUROTRANSMISSION
AMINO ACID SYNAPSE
Amino acids used by a neuron as neurotransmitters are compartmentalized for release as neurotransmitters in synaptic vesicles. The amino acid glutamate (depicted in this diagram) is the most abundant excitatory neurotransmitter in the CNS. Following release from synaptic vesicles, some glutamate binds to postsynaptic receptors. Released glutamate is inactivated by uptake into both pre- and postsynaptic neurons, where the amino acid is incorporated into the Krebs cycle or reused for a variety of functions. Glutamate also is taken up and recycled in the CNS by astrocytes.

CHEMICAL NEUROTRANSMISSION

CATECHOLAMINE SYNAPSE
Catecholamines are synthesized from the dietary amino acid tyrosine, which is taken up competitively into the brain by a carrier system. Tyrosine is synthesized into L-dopa by tyrosine hydroxylase (TH), the rate-limiting synthetic enzyme. Additional conversion into dopamine takes place in the cytoplasm via aromatic L-amino acid decarboxylase (ALAAD). Dopa- mine is taken up into synaptic vesicles and stored for subsequent release. In noradrenergic nerve terminals, dopamine beta-hydroxylase (DBH) further hydroxylates dopamine into norepinephrine in the synaptic vesicles. In adrenergic nerve terminals, norepinephrine is methylated to epinephrine by phenolethanolamine N-methyl transferase (PNMT). Following release, the catecholamine neurotransmitter binds to appropriate receptors (dopamine and alpha- and beta-adrenergic receptors) on the postsynaptic membrane, altering postsynaptic excitability, second-messenger activation, or both. Catecholamines also can act on presynaptic receptors, modulating the excitability of the presynaptic terminal and influencing subsequent neurotransmitter release. Catecholamines are inactivated by presynaptic reuptake (high-affinity uptake carrier) and, to a lesser extent, by metabolism (monoamine oxidase deamination and catechol-O-methyltransferase) and diffusion.

SEROTONIN SYNAPSE
Serotonin is synthesized from the dietary amino acid tryptophan, taken up competitively into the brain by a carrier system. Tryptophan is synthesized to 5-hydroxytryptophan (5-OH- tryptophan) by tryptophan hydroxylase (TrH), the rate limiting synthetic enzyme. Conversion of 5-hydroxytryptophan to 5-hydroxytryptamine (5-HT, serotonin) takes place in the cytoplasm by means of ALAAD. Serotonin is stored in synaptic vesicles. Following release, serotonin can bind to receptors on the postsynaptic membrane, altering postsynaptic excitability, second messenger activation, or both. Serotonin also can act on presynaptic receptors (5-HT receptors), modulating the excitability of the presynaptic terminal and influencing subsequent neurotransmitter release. Serotonin is inactivated by presynaptic reuptake (high-affinity uptake carrier) and to a lesser extent by metabolism and diffusion.

PEPTIDE SYNAPSES
Neuropeptides are synthesized from prohormones, large peptides synthesized in the cell body from mRNA. The larger precursor peptide is cleaved posttranslationally to active neuropeptides, which are packaged in synaptic vesicles and transported anterogradely by the process of axoplasmic transport. These vesicles are stored in the nerve terminals until released by appropriate excitation-secretion coupling induced by an action potential. The neuropeptide binds to receptors on the postsynaptic membrane. In the CNS, there is often an anatomic mismatch between the localization of peptidergic nerve terminals and the localization of cells possessing membrane receptors responsive to that neuropeptide, suggesting that the amount of release and the extent of diffusion may be important factors in neuropeptide neurotransmission. Released neuropeptides are inactivated by peptidases.

ACETYLCHOLINE (CHOLINERGIC) SYNAPSE
Acetylcholine (ACh) is synthesized from dietary choline and acetyl coenzyme A (CoA), derived from the metabolism of glucose by the enzyme choline acetyltransferase (ChAT). ACh is stored in synaptic vesicles; following release, it binds to cholinergic receptors (nicotinic or muscarinic) on the post-synaptic membrane, influencing the excitability of the post-synaptic cell. Enzymatic hydrolysis (cleavage) by acetylcholine esterase rapidly inactivates ACh.

CLINICAL POINT
Synthesis of catecholamines in the brain is rate limited by the avail- ability of the precursor amino acid tyrosine; synthesis of serotonin, an indoleamine, is rate limited by the availability of the precursor amino acid tryptophan. Tyrosine and tryptophan compete with other amino acids phenylalanine, leucine, isoleucine, and valine for uptake into the brain through a common carrier mechanism. When a good protein source is available in the diet, tyrosine is present in abundance, and robust catecholamine synthesis occurs; when a diet lacks sufficient protein, tryptophan is competitively abundant com- pared with tyrosine, and serotonin synthesis is favored. This is one mechanism by which the composition of the diet can influence the synthesis of serotonin as opposed to catecholamine and influence mood and affective behavior. During critical periods of development, if low availability of tyrosine occurs because of protein malnourishment, central noradrenergic axons cannot exert their trophic influence on cortical neuronal development such as the visual cortex; stunted dendritic development occurs, and the binocular responsiveness of key cortical neurons is prevented. Thus, nutritional content and balance are important to both proper brain development and ongoing affective behavior.