Acid-Sensing Ion Channels and Mechanosensation

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.

Acid-Sensing Ion Channel 2: Function and Modulation

“…Taken together, these findings demonstrate that a loss of ASIC2 results in hypertension and pressure-related renal injury [63,64]. Thus, ASIC2 is necessary for the proper maintenance of both blood pressure and renal perfusion [15].…”

“…In terms of protein structure for these extracellular domain subunits, they are made up of 12 β-sheets (β1-12), 7 α-helices (α1-7), and 7 disulfide bonds [11,13]. Furthermore, the wrist region connects the palm domain to the two TMs, consisting of six α-helix chains, and these two TMs make up the "pore" region of ASICs that allows sodium and calcium ion permeation [13][14][15]. Ion permeation is triggered by proton binding to the "acidic pocket" of ASIC, which is in the junction between the finger and thumb domain of one ASIC subunit and the palm domain of another subunit [16].…”

“…However, some of these examinations focused on ASIC1a [21,25]. It is reasonable to think that the ASIC2 variants could be specific therapeutic targets on their own, given that their physiology and pathology have been shown to involve pain modulation [27], mechanosensation [15], acidosis-induced neuronal death [17,28,29], and neurotransmission [22]. Expansion on the physiology, pathology, and modulation of ASIC2 will be informative for the field in assessing its viability as a potential therapeutic target.…”

“…The ASIC1a, ASIC2a, and ASIC2b subtypes are predominantly found in the brain, with the ASIC1a subtype being the most densely populated [11][12][13]. Investigation into these combinations showed that most functional ASICs in the striatum and cerebellum are ASIC1a homomers [10,15], whereas the majority in all other areas of the brain, such as the hippocampus and amygdala, are homotrimeric ASIC1a and ASIC1a/2 heterotrimers [9,10]. The non-functional ASIC2b subunit itself is expressed not only in the DRG, but also in the brain [29,30].…”

The Lamellar Cells of Vertebrate Meissner and Pacinian Corpuscles: Development, Characterization, and Functions

“…Channel complexes of the family of the degenerin/epithelial Na + channels (DEG/ENa + C) might be involved in mechanotransduction. Ion channel subunits and family branches of DEG/ENa + C [like acid-sensing ion channels (ASIC)] are gated by mechanical forces and, for this reason, have been proposed as mechanotransducers [see for a review, ( Ruan et al, 2021 )]. DEG/ENa + C subunits and ASIC2 have been detected in the lamellar cells of murine and human Pacinian corpuscles ( Montaño et al, 2009 ; Calavia et al, 2010 ) as well as in a subpopulation of human Meissner corpuscles ( Cabo et al, 2015 ).…”