Serotonin

I. Classification

Indoleamine: Serotonin (5-hydroxytryptamine) II. Distribution A. Central Distribution Cell bodies in midline pontine nuclei raphe cells. Ascending and descending projections to rest of brain and spinal cord.
 B. Peripheral localization (Only 2% of body 5-HT in brain) In enteric nervous system
In mast cells, blood platelets (not produced there) III. Synthesis A. Steps in Synthetic Pathway 1. Initial step is hydroxylation of tryptophan to 5-HTP via action of tryptophan hydroxylase
2. 5-HTP is decarboxylated to 5-HT via AADC.
3. Like DA, 5-HT is synthesized in the cytoplasm and must be stored in vesicles.
4. Try-OH is marker of 5-HT neurons. B. Rate-limiting step 1. Try-OH limiting in 5-HT synthesis a. Limiting factor may be availability of tryptophan
Km of try for enzyme is 30-60 µM
Concentration of Try in 5-HT cells is thought to be similar; thus enzyme probably not saturated. Increases in cerebral Try levels repeatedly results in increased synthesis of 5-HT. Brain use of Try represents only ~1% of total body utilization of tryptophan.
b. Try must compete with other dietary amino acids for uptake at level of capillary endothelial cells. Will increasing dietary tryptophan enhance 5-HT synthesis in the brain?
c. Availability of PtH4 may be secondary limiting factor

C. Regulation of 5-HT synthesis

1. No apparent end product inhibition of 5-HT onto TRY-OH
2. Enzyme activation linked to neural activity
a. Stimulation of specific cell groups in the raphe leads to enhanced TRY-OH activity in select 5-HT terminal regions.
b. Stimulation-induced increase is Ca++ dependent and probably linked to phosphorylation. Whether this changes Km or Vmax is a matter of contention.
 3. Long-term enzyme induction Partial destruction of 5-HT neurons results in an increase in TRY-OH mRNA in residual cells and increase in enzyme activity.

IV. Enzymatic degradation

A. Does not terminate synaptic action of released transmitters
B. Intracellular degradation by monoamine oxidase (mainly MAOA) metabolizes considerable amounts of intracellular 5-HT. Thus, measuring the ratio of 5-HIAA:5-HT is not a good index of 5-HT turnover, since much of the metabolite produced would not have come from released 5-HT.

V. Vesicular Storage

A. Serves Two Functions
B. Protects 5-HT from enzymatic degradation thus making transmitter available for release
C. Serotonin uptake into vesicles is not ATP dependent. 5-HT vesicles contain serotonin binding protein (SBP).
D. Different populations of vesicles have been identified 1. Large dense core vesicles (70-120) are believed to store 5-HT
2. small, translucent vesicles (40-60 nm) also seen, function unclear. VI. Synaptic inactivation A. 5-HT is cleared from synaptic cleft mainly by reuptake of transmitter back into the presynaptic terminal via a Na+ and energy dependent process. Energy requirement probably maintains sodium gradient across cells rather than drives carrier mechanism. Reaccumulated transmitter can be repackaged for release.
B. Carrier molecule may not be unique to 5-HT neurons. In periphery is located on blood platelets, which do not synthesize 5-HT. Astrocytes have also been shown to accumulate 5-HT.
C. Neither extracellular enzymatic degradation nor diffusion play a role in regulating synaptic levels of transmitter.

VII. Release

A. Calcium dependent
B. Related to firing rate of neuron
C. Influenced by presence of autoreceptors on presynaptic terminal
D. Vesicles mediate transmitter release 1. Upon depolarization of nerve terminal, Ca++ enters cell and this leads to fusion of vesicles with cell membrane. When 5-HT terminal is depolarized, SBP is released along with 5-HT; evidence of exocytosis.

VIII. General principle of neurotransmitter regulation

Transmitter synthesis, storage, release are all dynamic processes; the acute imbalances produced initially by interference with any one mechanism will soon be counteracted by the built-in feedback nature of the systems. Under continued interference, a new equilibrium state will be reached and responses to drugs may be different than initially.

Last modified: 9/10/97