ASIC2 Subunits Facilitate Expression at the Cell Surface and Confer Regulation by PSD-95

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.

ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents

“…ASIC2a generated distinct currents in response to an extracellular pH drop to 5.0 or more acidic pH, while ASIC3 displayed higher sensitivity to protons; the half-maximal pH value (pH 50 ) of the ASIC3 transient currents was 6.1 ± 0.2 (n=5), while the pH-dependency curve of ASIC2a did not reach a plateau even at pH 4.0, as previously reported (Fig. 3B) (22). The sustained currents of ASIC3 were steadily increased by a decreasing extracellular pH value, and it was significantly increased when a pH pulse of 4.0 was applied (Fig.…”

“…Recently, it has been reported that ASIC2a enhances the surface expression of ASIC1a (22, 23). To test whether ASIC2a can also deliver ASIC3 to the cell surface, we co-expressed ASIC2a and ASIC3 in HEK293T cells.…”

Novel Insights into Acid-Sensing Ion Channels: Implications for Degenerative Diseases

“…For instance, ASIC1a and ASIC3 are the most sensitive to H + channel proteins of these subunits than other ASIC members, which are activated by pH levels below 7.0 [33]. In contrast to ASIC1a homomers, ASIC2a shows low sensitivity to reduced extracellular pH (pH50=4.35) and slow channel inactivation [34,35]. Moreover, homomeric ASIC2a displays slower kinetics of desensitization than ASIC1a homomers [36,37].…”

“…ASIC2b does not form functional ion channels by itself, distinct from homomeric ASIC2a subunits [19]. On the other hand, ASIC2b associates with other ASIC subunits to form heteromultimeric channels with unique functional properties [19,35]. ASIC3 is primarily expressed in peripheral sensory neurons and plays an important role in pain perception, particularly high-intensity pain stimulation and acid-induced hyperalgesia [38].…”

Acid sensing ion channel 2: A new potential player in the pathophysiology of multiple sclerosis

“…When ASIC2a heteromultimerizes with other subunits, it reduces pH sensitivity. Furthermore, ASIC2 subunits facilitate subcellular localization of ASIC channels (Harding, Kusama, Hattori, Gautam, & Benson, 2014) through the interaction between ASIC2 and the neuronal scaffolding protein PSD-95, thus increasing ASIC1a localization in dendritic spines (Zha et al, 2009).…”