A proton-gated cation channel involved in acid-sensing

Abstract

Acid-sensing is associated with both nociception and taste transduction. Stimulation of sensory neurons by acid is of particular interest, because acidosis accompanies many painful inflammatory and ischaemic conditions. The pain caused by acids is thought to be mediated by H+-gated cation channels present in sensory neurons. We have now cloned a H+-gated channel (ASIC, for acid-sensing ionic channel) that belongs to the amiloride-sensitive Na+ channel/degenerin family of ion channels. Heterologous expression of ASIC induces an amiloride-sensitive cation (Na+ > Ca2+ > K+) channel which is transiently activated by rapid extracellular acidification. The biophysical and pharmacological properties of the ASIC channel closely match the H+-gated cation channel described in sensory neurons. ASIC is expressed in dorsal root ganglia and is also distributed widely throughout the brain. ASIC appears to be the simplest of ligand-gated channels.

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

“…Since the first subunit was cloned 10 years ago [13], six ASIC subunit proteins, encoded by four genes, have been identified: ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4. All ASICs belong to the degenerin/epithelial Na + channel (DEG/ENaC) superfamily, which are Na + -selective cation channels sensitive to amiloride [13,14].…”

“…All ASICs belong to the degenerin/epithelial Na + channel (DEG/ENaC) superfamily, which are Na + -selective cation channels sensitive to amiloride [13,14]. Though not exclusively, ASICs are highly expressed in peripheral sensory neurons and in the neurons of the central nervous system.…”

“…Though not exclusively, ASICs are highly expressed in peripheral sensory neurons and in the neurons of the central nervous system. In the peripheral sensory system, ASICs are enriched in dorsal root ganglion and trigeminal ganglion, whereas in the brain, high level of ASICs are expressed in cerebral cortex, cerebellum, hippocampus, amygdala, and olfactory bulb [13,15,16].…”

“…Based on the biochemical analysis of ENaC [13,17] and the glycosylation studies of ASIC2a subunits [18], the proposed membrane topology of each ASIC subunit consists of two transmembrane domains (TM I and TM II), linked by a large extracellular cystein-rich loop, and intracellular N and C termini. Functional ASICs are believed to be tetrameric assemblies of homomeric or heteromeric subunits [19] (Figure 1).…”

“…ASIC1a is widely expressed in the neurons of peripheral sensory and the central nervous system [13,16,22]. Homomeric ASIC1a channels respond to low pH o by mediating a fast and transient inward current with a threshold pH of ∼7.0, and the pH for half maximal activation (pH 0.5 ) at ∼6.2 [13].…”