Abstract
Acid-sensing ion channels (ASICs) are Na+ channels activated by changes in pH within the peripheral and central nervous systems. Several different isoforms of ASICs combine to form trimeric channels, and their properties are determined by their subunit composition. ASIC2 subunits are widely expressed throughout the brain, where they heteromultimerize with their partnering subunit, ASIC1a. However, ASIC2 contributes little to the pH sensitivity of the channels, and so its function is not well understood. We found that ASIC2 increased cell surface levels of the channel when it is coexpressed with ASIC1a, and genetic deletion of ASIC2 reduced acid-evoked current amplitude in mouse hippocampal neurons. Additionally, ASIC2a interacted with the neuronal synaptic scaffolding protein PSD-95, and PSD-95 reduced cell surface expression and current amplitude in ASICs that contain ASIC2a. Overexpression of PSD-95 also reduced acid-evoked current amplitude in hippocampal neurons. This result was dependent upon ASIC2 since the effect of PSD-95 was abolished in ASIC2−/− neurons. These results lend support to an emerging role of ASIC2 in the targeting of ASICs to surface membranes, and allows for interaction with PSD-95 to regulate these processes.
Highlights
Acid-sensing ion channels (ASICs) are H+-gated Na+-conducting ion channels predominantly expressed in the nervous systems of chordates
ASIC2a homomeric channels require very low pH values for activation, which is probably below the range achieved in vivo during physiological and even pathological conditions
When ASIC2a heteromultimerizes with other ASIC subunits, it generally reduces channel pH sensitivity, and when ASIC2b heteromultimerizes with other subunits, the pH sensitivity of activation is unaltered
Summary
ASICs are H+-gated Na+-conducting ion channels predominantly expressed in the nervous systems of chordates. 4 genes (ASIC1-4) encode for at least 6 different ASIC subunits [1]. ASIC1 and ASIC2 have alternative splice forms (ASIC1a and -1b; -2a and -2b, respectively), which differ in the intracellular N-termini and first transmembrane domains. In contrast to ASIC1a, ASIC3 is predominantly expressed in peripheral sensory neurons, where it contributes to pain sensation, including that from the heart and skeletal muscle [14,15,16,17,18]. ASIC4 does not contribute to H+gated currents, and its function in mammals is largely unknown [21,22]
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