Tissue acidosis (decrease in pH below the physiological level) that occurs in ischemia, tissue damage or inflammation is accompanied by pain. At the molecular level, H+-gated cation channels are activated by low pH in nociceptive neurons. H+-gated cation channels, members of the NaC/DEG superfamily of Na channels that include amiloride-sensitive epithelial Na+ channel proteins (alpha, beta, gamma and delta-ENaC subunits), are expressed in epithelia of the vertebrate kidney, colon, lung, tongue and brain. The ENaC subunits may form heterotrimeric active sodium channel. ENaCs are involved in sodium and water readsorption, and salty taste transduction. The superfamily of DEG/NaC proteins are characterized by intracellular N and C-termini, two TM domains, and a large extracellular loop.
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