Acid-induced CGRP release from the stomach does not depend on TRPV1 or ASIC3

Acid-sensing and regulating reactions are vitally important in the upper gastrointestinal tract and disturbances are common. Sensory neurons in the mucosa detect the intrusion of hydrogen ions and, by their release of vasoactive neuropeptides, seem to play a predominantly protective role in these tissues.

The model to investigate sensory transduction of proton stimuli in the isolated everted mouse stomach was to measure the induced calcitonin gene-related peptide (CGRP) release as an index of neuronal activation.

Proton concentrations in the range of pH 2.5-0.5 stimulated the release of CGRP and substance P and profoundly decreased the prostaglandin E2 formation in outbred CD mice. A similar linearly pH-dependent CGRP release was observed in inbred C57BL/6 mice, fully dependent on extracellular calcium at pH 2, partially at pH 1. Both transient receptor potential vanilloid type 1 (TRPV1) and acid-sensing ion channel type 3 (ASIC3) are expressed in the sensory neurons innervating the stomach walls and are responsible for the transduction of acidic stimuli in other visceral organs. However, the proton-induced gastric CGRP release in mice lacking the TRPV1 or the ASIC3 receptor-channels was the same as in corresponding wild-type mice. Nonetheless, the pharmacological blockers N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide and amiloride, respectively, inhibited the acid-stimulated CGRP release, although to the same extend in wild types as TRPV1 and ASIC3 knockout mice.

Adequate proton concentrations inhibit prostaglandin and stimulate CGRP release from the stomach wall, however, the transduction mechanism in the gastric sensory neurons remains unclear.