5-hydroxytryptamine receptor 4 (5-HT4R) (5-HT4R)

The 5-hydroxytryptamine receptor 4 (5-HT4R) is a G protein-coupled receptor (GPCR) that serves as a critical regulator of gastrointestinal (GI) motility and cardiac function [1, 3]. In the GI tract, 5-HT4R is primarily located on enteric neurons, where its activation triggers the release of acetylcholine, thereby enhancing the peristaltic reflex and accelerating gastric emptying and colonic transit [6, 10]. This biological role makes the receptor a key therapeutic target for motility disorders, including chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) [10, 11]. In the cardiovascular system, the receptor is predominantly expressed in the atria, where its activation increases heart rate and contractility through the stimulation of the adenylate cyclase/cAMP signaling pathway [13, 16]. The clinical development of 5-HT4R agonists has been significantly impacted by cardiovascular safety concerns [2, 5]. Early prokinetic agents such as cisapride were withdrawn from the market due to life-threatening arrhythmias resulting from off-target inhibition of hERG potassium channels, while tegaserod was restricted due to an association with ischemic cardiovascular events [10, 15]. Modern drug discovery efforts focus on highly selective 5-HT4R agonists, such as prucalopride, which aim to provide prokinetic benefits without these adverse cardiovascular effects [2, 10]. Additionally, research into the maladaptive upregulation of 5-HT4R in heart failure and atrial fibrillation suggests that 5-HT4R antagonists may have potential as future cardiovascular therapies [13, 16].

Other names

Serotonin receptor 4HTR45-HT45-HT4RCardiac 5-HT4 receptor

5-HT4 receptor agonists bind to the Gs-coupled 5-HT4 receptor, stimulating adenylate cyclase and increasing intracellular cyclic AMP (cAMP) levels [3, 11]. In the gastrointestinal tract, this leads to the release of excitatory neurotransmitters like acetylcholine from enteric neurons, which promotes peristalsis and improves motility [6, 10]. In the heart, 5-HT4 receptor activation in the atria increases the force and rate of contraction (positive inotropic and chronotropic effects) [13, 16].