5-hydroxytryptamine receptor 4 isoform b (5-HT4b) (5-HT4b)

The Human 5-HT4b receptor is a specific splice variant of the 5-hydroxytryptamine receptor 4, belonging to the Class A G protein-coupled receptor family [5, 12]. It is widely distributed in the human body, with significant expression in the gastrointestinal tract, the central nervous system, and the heart [6, 13]. Biologically, it primarily functions by stimulating adenylyl cyclase to increase intracellular cAMP levels, though the 'b' isoform is notable for its dual coupling to both Gs and Gi/o proteins [1, 3]. This signaling pathway modulates the release of various neurotransmitters, most notably acetylcholine in the enteric nervous system, which promotes gastrointestinal motility and peristalsis [4, 7]. In the heart, activation of 5-HT4b receptors contributes to positive inotropic and chronotropic effects, while in the brain, it is involved in memory and mood regulation [10, 11]. Therapeutically, the receptor is a key target for treating motility disorders such as chronic constipation and irritable bowel syndrome (IBS) using agonists like prucalopride [14, 19]. Historically, drugs targeting this receptor, such as cisapride and tegaserod, faced significant safety challenges due to cardiovascular risks, including QT prolongation and ischemic events [14, 19]. Modern drug development focuses on highly selective 5-HT4 agonists to minimize these off-target effects and improve the safety profile for patients with gastrointestinal dysfunction [19].

Other names

HTR45-HT4 receptor5-hydroxytryptamine receptor 4Serotonin receptor 45-HT4(b)

Agonism of the 5-HT4b receptor activates adenylyl cyclase via Gs proteins, increasing intracellular cAMP and facilitating the release of excitatory neurotransmitters like acetylcholine to enhance smooth muscle contraction and gastrointestinal transit [5, 7, 8].