Serotonergic (5HT) Receptors

SEROTONERGIC (5HT) RECEPTORS

Gaddum and Picarelli (1957) classified 5HT receptors into musculotropic (D type) and neurotropic (M type) on the basis of pharmacological criteria. The classical 5HT antagonists methysergide and cyproheptadine blocked D type receptors. Subsequently 5HT receptors were differentiated by their high or low affinity for [3H] 5HT in radioligand binding studies. The present system of classifying 5HT receptors is based on molecular characterization and cloning of the receptor cDNAs.

Four families of 5HT receptors (5HT₁, 5HT₂, 5HT₃, 5HT₄₇) comprising of 14 receptor subtypes have so far been recognized. However, only some of these have been functionally correlated or their selective agonists/antagonists defined. Knowledge of subtypes of 5HT receptors has assumed importance because some newly developed therapeutically useful drugs can only be described as 5HT receptor subtype selective agonists or antagonists.

All 5HT receptors (except 5HT₃) are G protein coupled receptors which function through decreasing (5HT₁) or increasing (5HT₄, 5 HT₆, 5HT₇) cAMP production or by generating IP₃/ DAG (5HT₂) as second messengers. The 5HT₃ is ligand gated cation (Na+,K+) channel which on activation elicits fast depolarization.

5HT₁ Receptors

Five subtypes (5HT_{1A, B, D, E, F}) have been identified. The 5HT_1C receptor is now designated 5HT_2c. All subtypes of 5HT₁ receptor inhibit adenylyl cyclase; 5HT_1A in addition activates K+ channels (resulting in hyperpolarization) and inhibits Ca2+ channels. These receptors function primarily as autoreceptors in brain— inhibit firing of 5HT neurones or release of 5HT from nerve endings.

The most important location of 5HT_1A receptor are raphe nuclei of brainstem and hippocampus. The antianxiety drug buspirone acts as a partial agonist of 5HT_1A receptor. The 5HT_1D receptor has been shown to regulate dopaminergic tone in substantia nigra–basal ganglia, and

5HT_1B/1D to cause constriction of cranial blood vessels. The antimigraine drug sumatriptan is a selective 5HT_1B/1D agonist. Other functions subserved by 5HT _1D receptors are inhibition of NA release from sympathetic nerve endings and that of inflammatory neuropeptides from nerve endings in cranial blood vessels.

5HT₂ Receptors

There are 3 subtypes of 5HT₂ receptor; all are coupled to phospholipase C and function through generation of IP₃/DAG. 5HT_2A receptor also inhibits K⁺ channels resulting is slow depolarization of neurones. αmethyl 5HT is a selective agonist for all 3 subtypes.

5 HT_2A is the most widely expressed postjunctional 5HT receptor (designated earlier as D type) located on vascular and visceral smooth muscle, platelets and cerebral neurones especially prefrontal cortex. It mediates most of the direct actions of 5HT like vasoconstriction, intestinal, uterine and bronchial contraction, platelet aggregation and activation of cerebral neurones. Ketanserin is a 5HT₂ antagonist more selective for 5HT_2A.

Contraction of rat gastric fundus is mediated by 5HT_2B receptor.

5HT_2C receptor is located on vascular endothelium— elicits vasodilatation through EDRF release. Choroid plexus expresses large number of 5HT_2C receptors.

5HT₃ Receptor

This is the neuronal 5HT receptor which rapidly depolarizes nerve endings by opening the cation channel located within it and corresponds to the original M type receptor. It mediates the indirect and reflex effects of 5HT at:

·        Somatic and autonomic nerve endings → pain, itch, coronary chemoreflex (bradycardia, fall in BP due to withdrawal of sympathetic tone, respiratory stimulation or apnoea elicited by stimulation of receptors in the coronary bed), other visceral reflexes.

·        Nerve endings in myenteric plexus → augmentation of peristalsis, emetic reflex.

·        Area postrema and nucleus tractus solitarious in brainstem → nausea, vomiting.

Ondansetron is a selective 5HT₃ antagonist which inhibits vomiting by blocking these receptors in brainstem as well as in gut wall. 2Methyl 5HT is a selective 5HT₃ agonist.

5HT_4–7 Receptors

The 5HT₄ receptor has been demonstrated in the mucosa, plexuses and smooth muscle of the gut → probably involved in augmenting intestinal secretion and peristalsis. It is also located in brain, especially hippocampus and the colliculi where it causes slow depolarization by decreasing K+ conductance.

Cisapride and renzapride are selective 5HT₄  agonists. The recently cloned 5HT₅, 5HT₆ and 5HT₇ receptors are closely related to the 5HT₄ receptor. These are mainly located in specific brain areas, but their functional role is not known. An interesting finding is that clozapine (atypical neuroleptic) has high affinity for 5HT₆ and 5HT₇ receptors in addition to being a 5HT_2A/2C antagonist.