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.
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.
