Yes, 5-HT4 Receptors Are Present in the Stomach
5-HT4 (5-hydroxytryptamine 4) receptors are definitively present in the human stomach, where they play a crucial role in regulating gastric motility and emptying. This is evidenced by the clinical efficacy of selective 5-HT4 receptor agonists in accelerating gastric emptying in patients with gastroparesis 1.
Direct Evidence of Gastric 5-HT4 Receptor Presence
5-HT4 receptor agonists directly stimulate peristalsis in the stomach through activation of these receptors, which work by releasing acetylcholine from the myenteric plexus 1.
Multiple selective 5-HT4 receptor agonists have demonstrated pharmacodynamic effects specifically on gastric emptying, confirming functional receptor presence:
- Velusetrag accelerated gastric emptying in a large phase 2 randomized controlled trial in gastroparesis patients 1.
- Prucalopride accelerated gastric emptying and improved symptoms in both diabetic and idiopathic gastroparesis 1.
- Felcisetrag significantly accelerated gastric emptying T1/2 compared to placebo in patients with documented delayed gastric emptying 2.
- Tegaserod, a partial 5-HT4 receptor agonist, enhances gastric emptying 1.
Functional Characterization in Human Gastric Tissue
Direct neuromuscular studies in human isolated gastric antrum demonstrate that 5-HT4 receptor agonists facilitate cholinergically-mediated contractions 3.
In human gastric circular muscle, the selective 5-HT4 agonist prucalopride facilitated contractions by 42 ± 9% in the absence of NO synthase inhibition and 55 ± 13% in its presence, with effects blocked by the 5-HT4 antagonist SB204070 3.
Metoclopramide, which acts partly through 5-HT4 receptors (in addition to D2 antagonism), facilitated contractions by 95 ± 29% in human gastric tissue, with this facilitation prevented by 5-HT4 receptor blockade 3.
Clinical Relevance in Gastrointestinal Disorders
5-HT4 receptors represent important therapeutic targets for gastroparesis and other gastric motility disorders, as these receptors are present throughout the gastrointestinal tract including the stomach 4, 5.
The therapeutic potential of 5-HT4 receptor agonists extends beyond the colon to include gastric dysmotility, functional dyspepsia, and gastroparesis 4, 5.
Receptor Distribution Throughout the GI Tract
5-HT4 receptors are distributed throughout the entire gastrointestinal tract, not just the colon, making them targets for treating motility disorders at multiple levels including the stomach 5, 6.
New-generation selective 5-HT4 receptor agonists demonstrate tissue selectivity, behaving as partial or full agonists depending on receptor density and coupling efficiency in different GI tissues 6.