Synthesis And Metabolism

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5-HT is synthesized by a two-step pathway from tryptophan (Figure 11-1), which is actively transported into the brain by a carrier protein that also transports other large neutral and branched-chain amino acids. Tryptophan hydroxylase, a mixed-function oxidase that requires O2 and a reduced pteridine cofactor, is the rate-limiting enzyme in the synthetic pathway. Unlike tyrosine hydroxylase, tryptophan hydroxylase is not regulated by end-product inhibition, although regulation by phosphorylation is common to both enzymes. Brain tryptophan hydroxylase is not generally saturated with substrate; consequently the concentration of tryptophan in the brain influences the synthesis of 5-HT.

The enzyme that converts l-5-hydroxytryptophan to 5-HT, aromatic l-amino acid decarboxylase, is the same enzyme that decarboxylates l-dopa in catecholamine synthesis (see Chapter 6). 5-HT is stored in secretory granules by a vesicular transporter and released by exocytosis. The action of released 5-HT is terminated by neuronal uptake mediated by a specific 5-HT transporter localized in the membrane of serotonergic axon terminals (where it terminates the action of 5-HT in the synapse) and in the membrane of platelets (where it takes up 5-HT from the blood). This uptake system is the only way that platelets acquire 5-HT (they lack the enzymes required to synthesize 5-HT). The 5-HT transporter, SERT, has been cloned (see Chapters 2 and 12).

The principal route of metabolism of 5-HT involves oxidative deamination by MAO, with subsequent conversion of the aldehyde to 5-hydroxyindole acetic acid (5-HIAA) by an aldehyde dehydrogenase (Figure 11-1). Reduction of the acetaldehyde to an alcohol, 5-hydroxytryptophol, is normally insignificant. 5-HIAA is actively transported out of the brain by a process that is sensitive to probenecid. Since 5-HIAA formation accounts for nearly 100% of the metabolism of 5-HT in brain, the turnover rate of brain 5-HT is estimated by measuring the rate of rise of 5-HIAA after administration of probenecid. 5-HIAA from brain and peripheral sites of 5-HTstor-age and metabolism is excreted in the urine (range of urinary excretion of 5-HIAA by a normal adult, 2-10 mg/day). Larger amounts are excreted by patients with carcinoid syndrome, providing a reliable diagnostic test for the disease. Ingestion of ethyl alcohol results in elevated amounts of nicotinamide adenine dinucleotide (NADH), which diverts 5-hydroxyindole acetaldehyde from the oxidative route to the reductive pathway, increasing excretion of 5-hydroxytryptophol and reducing excretion of 5-HIAA. MAO-A preferentially metabolizes 5-HT and NE. Neurons contain both isoforms of monoamine oxidase (MAO-A and MAO-B); MAO-B is the principal isoform in platelets.

A close relative of 5-HT, melatonin (5-methoxy-N-acetyltryptamine), is formed by sequential N-acetylation and O-methylation (Figure 11-1). Melatonin is the principal indoleamine in the pineal gland, where it may be said to constitute a pigment of the imagination. External factors including environmental light control melatonin synthesis. Melatonin induces pigment lightening in skin cells and suppresses ovarian functions; it also serves a role in regulating biological rhythms and shows promise in the treatment of jet lag and other sleep disturbances.


The multiple 5-HT receptor subtypes comprise the largest known neurotransmitter-receptor family. 5-HT receptor subtypes are expressed in distinct but often overlapping patterns and couple to different transmembrane-signaling mechanisms (Table 11-1). Four 5-HT receptor families are recognized: 5-HTj through 5-HT4. The 5-HT1, 5-HT2, and 5-HT4-7 receptor families are members of the superfamily of GPCRs (see Chapter 1). The 5-HT3 receptor, on the other hand, is a ligand-gated ion channel that gates Na+ and K+ and has a predicted membrane topology akin to that of the nicotinic cholinergic receptor (see Chapter 9).

5-HTj RECEPTORS All 5 members of the 5-HT1 receptor subfamily inhibit adenylyl cyclase. At least one 5-HT1 receptor subtype, the 5-HT1A receptor, also activates a receptor-operated K+ channel and inhibits a voltage-gated Ca2+ channel, a common property of receptors coupled to

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