Zn2+ and H+ Are Coactivators of Acid-sensing Ion Channels

Abstract

Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular protons. They are expressed in sensory neurons, where they are thought to be involved in pain perception associated with tissue acidosis. They are also expressed in brain. A number of brain regions, like the hippocampus, contain large amounts of chelatable vesicular Zn 2؉ . This paper shows that Zn 2؉ potentiates the acid activation of homomeric and heteromeric ASIC2a-containing channels (i.e. ASIC2a, ASIC1a؉2a, ASIC2a؉3), but not of homomeric ASIC1a and ASIC3. The EC 50 for Zn 2؉ potentiation is 120 and 111 M for the ASIC2a and ASIC1a؉2a current, respectively. Zn 2؉ shifts the pH dependence of activation of the ASIC1a؉2a current from a pH 0.5 of 5.5 to 6.0. Systematic mutagenesis of the 10 extracellular histidines of ASIC2a leads to the identification of two residues (His-162 and His-339) that are essential for the Zn 2؉ potentiating effect. Mutation of another histidine residue, His-72, abolishes the pH sensitivity of ASIC2a. This residue, which is located just after the first transmembrane domain, seems to be an essential component of the extracellular pH sensor of ASIC2a.

Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a

“…1B), with a half-maximal effect at approximately pH 5.9. This value is in the same range as previously reported relationships between pH and ASIC1a current activation (2,23,30,32).…”

“…Indeed, transient acidification of the extracellular space has been reported during stimulation of hippocampal slices and isolated hippocampal neurons (11,12). The activity of these channels is also modulated by FMRFamide (Phe-MetArg-Phe-NH 2 )-related peptides and extracellular zinc ions (13,32,40), which might further enhance activity and hence Ca 2ϩ entry. It is also possible that other ligands will regulate the activity of these channels.…”

Heteromultimers of DEG/ENaC subunits form H + -gated channels in mouse sensory neurons

“…As sensory transducers, DEG͞ENaC channels provide potential targets for the pharmacological modulation of sensory stimuli, including pain. Their function can be altered by several agents, including FMRFamide (Phe-Met-Arg-Phe-NH2) and related neuropeptides (15), psalmotoxin 1 (27), cold temperature (29), Zn 2ϩ (30), lactate (31), and nonsteroidal anti-inflammatory drugs (32). In some cases, modulation is specific to the subunit composition of the channel.…”

Extracellular Zn2+ Activates Epithelial Na+ Channels by Eliminating Na+ Self-inhibition

“…We anticipate that future studies will address whether other members of ENaC/DEG family are also regulated by external transition metals. For example, extracellular Zn 2ϩ facilitates H ϩ activation of the acid sensing ionic channels that are homologous to ENaCs (21).…”