5-hydroxytryptamine receptor 1D (5-HT1D) (5-HT1D)

The 5-hydroxytryptamine receptor 1D (5-HT1D) is a G protein-coupled receptor (GPCR) that serves as a key mediator of serotonergic signaling in the human nervous system (UniProt P28221). It is primarily coupled to Gi/o proteins, which inhibit adenylyl cyclase activity and reduce intracellular cAMP levels upon ligand binding (IUPHAR/BPS Guide to Pharmacology). The 5-HT1D receptor is highly relevant in the pathophysiology of migraines, as it is localized on the presynaptic terminals of trigeminal sensory neurons where it modulates the release of pro-inflammatory neuropeptides such as calcitonin gene-related peptide (CGRP) (PubMed PMID: 15504140). Therapeutic agents known as triptans, such as sumatriptan and zolmitriptan, act as agonists at both 5-HT1B and 5-HT1D receptors to abort acute migraine attacks by inducing cranial vasoconstriction and inhibiting dural inflammation (StatPearls NBK554507). While 5-HT1B is more prominently involved in vascular contraction, 5-HT1D is thought to play a more significant role in the neuronal inhibition of pain transmission. Beyond its role in headache disorders, 5-HT1D has been studied for its involvement in psychiatric conditions and the regulation of other neurotransmitters like glutamate and GABA (NCBI Gene 3352).

Other names

HTR1D5-HT1D receptorSerotonin receptor 1D5-hydroxytryptamine receptor 1D alphaG-protein coupled receptor 7

Agonism of the 5-HT1D receptor inhibits the release of vasoactive neuropeptides (such as CGRP) from trigeminal perivascular nerve terminals and contributes to the stabilization of the trigeminovascular system, thereby relieving acute migraine symptoms (PubMed PMID: 10448300, StatPearls NBK554507).