5-hydroxytryptamine receptor 4 isoform a (5-HT4aR)

The Human 5-HT4a receptor is a specific splice variant of the 5-hydroxytryptamine receptor 4, a G protein-coupled receptor (GPCR) that plays a pivotal role in both the central and peripheral nervous systems (UniProt, 2024). Encoded by the HTR4 gene, this receptor is primarily coupled to the Gs protein, meaning its activation stimulates adenylate cyclase and increases intracellular cyclic AMP (cAMP) levels (Patsnap Synapse, 2024). In the gastrointestinal tract, the 5-HT4a receptor is involved in the regulation of the peristaltic reflex and the enhancement of intestinal motility, making it a key therapeutic target for disorders such as chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) (PubMed, 2012). In the central nervous system, it is highly expressed in regions like the hippocampus and amygdala, where it modulates the release of neurotransmitters such as acetylcholine and dopamine, thereby influencing cognitive functions and mood (PMC, 2018). Drugs targeting this receptor include prokinetic agonists like prucalopride and tegaserod, though early agents faced significant safety concerns regarding cardiovascular toxicity and arrhythmias (PubMed, 2023). Current research continues to explore the potential of selective 5-HT4a modulation for treating neurodegenerative diseases like Alzheimer's and psychiatric conditions like depression (MDPI, 2023). The receptor's diverse expression and functional profile make it a versatile target for both gastrointestinal and neurological drug development. Safety monitoring, particularly for cardiovascular effects, remains a critical component of therapeutic strategies involving 5-HT4a modulators.

Other names

HTR4 isoform aSerotonin receptor 4 isoform a5-HT4a receptor5-HT4(a) receptorHTR4A5-HT4(A)

Agonism of the 5-HT4 receptor stimulates Gs-protein signaling, leading to increased adenylate cyclase activity and elevated intracellular cAMP, which promotes smooth muscle contraction in the GI tract and enhances neurotransmitter release in the CNS; Antagonism blocks these effects (Patsnap Synapse, 2024; UniProt, 2024).