Acid-sensing ion channel 3: An analgesic target

Abstract

Acid-sensing ion channel 3 (ASIC3) belongs to the epithelial sodium channel/degenerin (ENaC/DEG) superfamily. It consists of one of 7 different ASIC subunits encoded by 5 different genes. Most ASIC subunits form trimeric ion channels that upon activation by extracellular protons mediate a transient inward current inducing cellular excitability. ASIC subunits exhibit differential tissue expression and biophysical properties, and the ability of subunits to form homo-and heteromeric trimers further increases the complexity of currents measured and their pharmacological properties. ASIC3 is of particular interest, not only because it exhibits high expression in sensory neurones, but also because upon activation it does not fully inactivate: a transient current is followed by a sustained current that persists during a period of extracellular acidity, i.e. ASIC3 can encode prolonged acidosis as a nociceptive signal. Furthermore, certain mediators sensitise ASIC3 enabling smaller proton concentrations to activate it and other mediators can directly activate the channel at neutral pH. Moreover, there is a plethora of evidence using transgenic mouse models and pharmacology, which supports ASIC3 as being a potential target for development of analgesics. This review will focus on current understanding of ASIC3 function to provide an overview of how ASIC3 contributes to physiology and pathophysiology, examining the mechanisms by which it can be modulated, and highlighting gaps in current understanding and future research directions.

Acid-Sensing Ion Channels and Mechanosensation

“…ASIC3 has been a heavily studied ion channel due to its wide distribution in the PNS [ 128 ] and connections to mechanosensation [ 4 ], especially ASIC3 involved in pain modulation. Although the data from different pain models regarding the ASIC3 involvement are mixed, ASIC3 largely contributes to pain modulation (see reviews) [ 129 , 130 , 131 , 132 , 133 ]. In the DRG, ASIC3 transduces mechanosensation through ECM-induced neuron stretching instead of direct neuron indentation [ 134 ].…”

Dexmedetomidine Inhibits ASIC Activity via Activation of α2A Adrenergic Receptors in Rat Dorsal Root Ganglion Neurons

“…Amiloride, a non-selective ASIC inhibitor, can significantly alleviate the pain caused by moderate (up to pH 6.0) pH, suggesting that ASICs, rather than TRPV1 or other acid sensors, mainly mediate the pain sensation ( Ugawa et al, 2002 ; Deval et al, 2008 ). ASICs, especially ASIC3, are the major player in pain associated with tissue acidosis and represent novel potential targets for development of analgesics ( Reeh and Steen, 1996 ; Wemmie et al, 2013 ; Li and Xu, 2015 ; Dulai et al, 2020 ).…”

A standardized extract of Centella asiatica (ECa 233) prevents temporomandibular joint osteoarthritis by modulating the expression of local inflammatory mediators in mice

“…8 Furthermore, ASIC3 can effectively transduce the prolonged tissue acidosis occurring in osteoarthritis pathology. 9 Synthesis of the calcitonin gene-related peptide (CGRP) is activated by nerve damage and enhanced by inflammatory mediators, such as bradykinin, serotonin, and interleukins (IL) -released after tissue injury-especially in the cell membrane of chondrocytes. [7][8][9] Moreover, CGRP also promotes TRPV1 upregulation 9,10 and ASIC3 expression.…”

“…9 Synthesis of the calcitonin gene-related peptide (CGRP) is activated by nerve damage and enhanced by inflammatory mediators, such as bradykinin, serotonin, and interleukins (IL) -released after tissue injury-especially in the cell membrane of chondrocytes. [7][8][9] Moreover, CGRP also promotes TRPV1 upregulation 9,10 and ASIC3 expression. 7,10 TRPV1 and ASIC3 are inflammatory markers triggered by compression injuries, which are the main causes of TMJ-OA.…”