Acid sensing by visceral afferent neurones

Abstract

Acidosis in the gastrointestinal tract can be both a physiological and pathological condition. While gastric acid serves digestion and protection from pathogens, pathological acidosis is associated with defective acid containment, inflammation and ischaemia. The pH in the oesophagus, stomach and intestine is surveyed by an elaborate network of acid-sensing mechanisms to maintain homeostasis. Deviations from physiological values of extracellular pH (7.4) are monitored by multiple acid sensors expressed by epithelial cells and sensory neurones. Protons evoke multiple currents in primary afferent neurones, which are carried by several acid-sensitive ion channels. Among these, acid-sensing ion channels (ASICs) and transient receptor potential (TRP) vanilloid-1 (TRPV1) ion channels have been most thoroughly studied. ASICs survey moderate decreases in extracellular pH whereas TRPV1 is activated only by severe acidosis resulting in pH values below 6. Other molecular acid sensors comprise TRPV4, TRPC4, TRPC5, TRPP2 (PKD2L1), epithelial Na(+) channels, two-pore domain K(+) (K₂(P)) channels, ionotropic purinoceptors (P2X), inward rectifier K(+) channels, voltage-activated K(+) channels, L-type Ca²(+) channels and acid-sensitive G-protein-coupled receptors. Most of these acid sensors are expressed by primary sensory neurones, although to different degrees and in various combinations. As upregulation and overactivity of acid sensors appear to contribute to various forms of chronic inflammation and pain, acid-sensitive ion channels and receptors are also considered as targets for novel therapeutics.