5-hydroxytryptamine receptor 4 isoform D (5-HT4D)

The 5-hydroxytryptamine receptor 4 isoform D (5-HT4D) is a specific splice variant of the 5-HT4 receptor, a G protein-coupled receptor (GPCR) that primarily couples to the Gs protein to stimulate adenylyl cyclase and increase intracellular cAMP levels [1.1.2, 1.3.1]. This isoform is distinguished by its "ultrashort" C-terminal tail, consisting of only two amino acids after the common splice site, which significantly influences its internalization, desensitization, and signaling efficiency compared to other isoforms [1.2.1, 1.3.1, 1.3.5]. In the central nervous system, 5-HT4D is of significant interest for its role in Alzheimer's disease; its activation has been shown to promote the non-amyloidogenic processing of amyloid precursor protein (APP), thereby increasing the secretion of neuroprotective sAPPalpha and reducing the production of neurotoxic beta-amyloid peptides [1.2.1, 1.4.1]. Peripherally, the 5-HT4D isoform is notably overexpressed in aldosterone-producing adrenocortical adenomas, suggesting a role in the regulation of adrenal steroidogenesis and potential as a diagnostic biomarker [1.3.1]. Drugs targeting the 5-HT4 receptor family, such as the agonists prucalopride and tegaserod, are clinically used to treat gastrointestinal motility disorders like chronic constipation and irritable bowel syndrome [1.2.2, 1.4.5]. The unique functional profile of the 5-HT4D isoform, particularly its impact on amyloid processing and its specific expression patterns, makes it a compelling target for the development of disease-modifying therapies in neurodegeneration and specialized endocrine conditions [1.2.1, 1.3.1].

Other names

5-HT4DHTR4D5-hydroxytryptamine receptor 4 isoform DSerotonin 4 receptor isoform DHTR4 splice variant DSerotonin 4 receptor – 5-HT4D isoform

The 5-HT4D receptor is a Gs-coupled G protein-coupled receptor (GPCR) that, upon activation by serotonin or synthetic agonists, stimulates adenylyl cyclase to increase intracellular cyclic AMP (cAMP) levels [1.1.2, 1.3.1]. This increase in cAMP activates protein kinase A (PKA) and other downstream effectors, leading to the modulation of neurotransmitter release (such as acetylcholine and dopamine) and the activation of signaling pathways like the ERK/MAPK pathway [1.1.2, 1.2.2]. Specifically, in the context of Alzheimer's disease, 5-HT4D activation promotes the alpha-secretase-mediated cleavage of amyloid precursor protein (APP), which favors the production of neuroprotective sAPPalpha over neurotoxic beta-amyloid peptides [1.2.1].