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Review
. 2021 May 1;22(9):4810.
doi: 10.3390/ijms22094810.

Acid-Sensing Ion Channels and Mechanosensation

Nina Ruan  1 , Jacob Tribble  1 , Andrew M Peterson  1 , Qian Jiang  1 , John Q Wang  1 , Xiang-Ping Chu  1
Affiliations
Review

Acid-Sensing Ion Channels and Mechanosensation

Nina Ruan et al. Int J Mol Sci. .

Abstract

Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer's disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.

Keywords: acid-sensing ion channels; mechanosensation; neurodegenerative diseases; nociception.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
An Acid-Sensing Ion Channels (ASICs) subunit has a “clenched fist” conformation with six domains: wrist, finger, β-ball, thumb, knuckle, and palm domains. Combined, these subunits form a heterotrimeric or homotrimeric structure to help recognize extracellular ligands and regulate proton-gated currents. With the inhibition of the “thumb” component of an ASICs subunit, such as with PcTx1 or Hm3a, there will be an inhibition of certain ASICs channels. PcTx1 leads to the inhibition of ASIC1a, whereas Hm3a leads to the inhibition of both ASIC1a and ASIC1b and additionally higher levels of stability over a span of 48 h.
Figure 2
Figure 2
The mechanotransduction model found in Caenorhabditis elegans is the leading theory on the ASICs mechanosensation model in humans. On the left, as found in Caenorhabditis elegans, MEC-4 and MEC-10 are DEG/ENaC proteins that connect to touch receptor neurons and eventually act with a gating-spring mechanism to activate ASICs for mechanosensation. Similarly, intracellularly in nematodes, there are found to be MEC-2, MEC6, and UNC-24 accessory subunit proteins that loosely associate with ASICs to activate mechanosensation via a similar mechanism as well. Conversely, in mammals, ASICs are shown to contain STOML1 and STOML3 proteins which correlate with nematode accessory subunit proteins and help activate ASICs for mechanosensation as well.
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