ASIC‐like, proton‐activated currents in rat hippocampal neurons

Abstract

The expression of mRNA for acid sensing ion channels (ASIC) subunits ASIC1a, ASIC2a and ASIC2b has been reported in hippocampal neurons, but the presence of functional hippocampal ASIC channels was never assessed. We report here the first characterization of ASIC‐like currents in rat hippocampal neurons in primary culture. An extracellular pH drop induces a transient Na+ current followed by a sustained non‐selective cation current. This current is highly sensitive to pH with an activation threshold around pH 6.9 and a pH0.5 of 6.2. About half of the total peak current is inhibited by the spider toxin PcTX1, which is specific for homomeric ASIC1a channels. The remaining PcTX1‐resistant ASIC‐like current is increased by 300 μm Zn2+ and, whereas not fully activated at pH 5, it shows a pH0.5 of 6.0 between pH 7.4 and 5. We have previously shown that Zn2+ is a co‐activator of ASIC2a‐containing channels. Thus, the hippocampal transient ASIC‐like current appears to be generated by a mixture of homomeric ASIC1a channels and ASIC2a‐containing channels, probably heteromeric ASIC1a+2a channels. The sustained non‐selective current suggests the involvement of ASIC2b‐containing heteromeric channels. Activation of the hippocampal ASIC‐like current by a pH drop to 6.9 or 6.6 induces a transient depolarization which itself triggers an initial action potential (AP) followed by a sustained depolarization and trains of APs. Zn2+ increases the acid sensitivity of ASIC channels, and consequently neuronal excitability. It is probably an important co‐activator of ASIC channels in the central nervous system.

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

“…In cortical and hippocampal neurons, however, knockout of ASIC1 gene alone almost completely eliminated the acid-activated current [10,22,32], suggesting that ASIC1a is a predominant functional ASIC subunit in CNS neurons. Further studies suggest that the acid-activated currents in CNS neurons are largely mediated by a combination of ASIC1a homomeric channels and ASIC1a/ASIC2a heteromeric channels [32,33]. ASIC1a is key in establishing the current amplitude.…”

“…Since all ASICs are Na + -selective channels which have a reversal potential near Na + equilibrium potential (∼ +60 mV), activations of ASICs at normal resting potentials produce exclusively inward currents which result in membrane depolarization and the excitation of neurons [33,34]. For homomeric ASIC1a channels, acid activation also induces Ca 2+ entry directly through these channels [10,12,13].…”

Increased hyperpolarized [1‐13C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13C‐labelled bicarbonate

“…Sensory neurones express several acid sensors: acid‐sensing ion channels (ASICs), transient receptor potential vanilloid 1 (TRPV1), proton‐sensing GPCRs and certain background K + channels 18. Furthermore, response to low pH has been shown to be sensitized by inflammatory mediators 19, 20, 21, 22, 23, 24…”

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

“…In cultured neurons, recombinant ASIC1a can be found on the cell body, but it also localizes to dendrites and is present at synapses (6). In central neurons, ASIC1a forms both homomultimers and heteromultimers with ASIC2a (7)(8)(9)(10). These complexes generate cation channels that are activated by a fall in the extracellular pH.…”