There are four broad ‘superfamilies’ of receptor: (1) the channel-linked (ionotropic) receptors; (2) the G-protein coupled (metabotropic) receptors; (3) the kinase-linked receptors; and (4) receptors that regulate gene transcription. The 5-HT1, 2, 4, 5, 6 and 7 receptors belong to the G-protein coupled superfamily. They are membrane receptors that have 7 transmembrane spanning a-helices. 5-HT binding to the ‘binding groove’ on the extracellular portion of the receptor activates the G-proteins, which initiate secondary messenger signalling pathways. The downstream effect is either inhibitory or stimulatory, depending on the type of G-protein linked to the receptor – 5-HT1 receptors are linked to inhibitory G-proteins, whereas 5-HT2, 4, 6 and 7 are linked to stimulatory G-proteins.
References
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The 5-HT3 receptor is distinct from the other 5-HT receptor subtypes, in that it is a ligand-gated ion channel that is permeable to sodium and potassium. The 5-HT3 receptor is structurally similar to the nicotinic acetylcholine receptor and is composed of 5 subunits. Two subunits have been cloned, 5-HT3A and 5-HT3B, and homomeric (5-HT3A) and heteromeric (5-HT3A/5-HT3B) forms of the receptor have both been characterised
Binding of an agonist at the 5-HT binding site causes a conformational change and activation of the 5-HT3 receptor. As a ligand gated ion channel this permits the movement of positively charged ions from the synaptic cleft into the cytoplasm. Binding of an antagonist at the 5-HT binding site prevents this activation and cell depolarisation is inhibited.
A 5-HT1A receptor antagonist prevents the activation of the 5-HT1A receptor. The 5-HT1A receptor is coupled to inhibitory G-proteins, which dissociate from the receptor on agonist binding, and inhibit secondary messenger signaling mechanisms. Antagonist binding inhibits this usual process, resulting in cell depolarisation.
Binding of a partial agonist to the 5-HT1A receptor causes the dissociation of inhibitory G-proteins. The G-protein alpha sub-unit binds to and inhibits adenylate cyclase. This prevents the conversion of ATP to cAMP and the initiation of other secondary messenger signaling mechanisms, hence cell depolarisation is inhibited.
A 5-HT2 receptor antagonist prevents the activation of the 5-HT2 receptor. The 5-HT2 receptor is coupled to stimulatory G-proteins, which dissociate from the receptor on agonist binding, and initiate secondary messenger signaling mechanisms. This causes cell depolarisation, which is inhibited by antagonist binding.
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