Acid-sensing ion channels (ASICs) are proton-gated subpopulations of the degenerate/epithelial sodium channel family. ASICs are cation channels that are activated by extracellular H+ and are composed of trimeric protein complexes composed of different subunits. ASIC1A is a key subunit of ASICs, and its role in the pathophysiology of many peripheral diseases is constantly being discovered. The family members of ASICs are largely transparent to Na+, and only ASIC1A is less transparent to Ca2+. Acid-base balance is a necessary condition for the body to maintain normal physiological activities. Various diseases caused by ischemia, hypoxia, and inflammation are associated with tissue acidification. ASIC1A is a key receptor for extracellular receptor protons, and acidosis-mediated cell damage is inextricably linked to its activation of Ca2+.
Structure and Distribution of ASIC1A
ASIC1A is composed of more than 500 amino acids and contains two hydrophobic transmembrane domains (TM1 and TM2) and one large cysteine-rich extracellular loop. Both the N-terminus and the C-terminus are intracellular, and the three subunits are required for the formation of a functional channel. The coral snake toxin MitTx is a heterodimeric polypeptide toxin that activates the ASIC1A channel in nanomolar concentrations in a pH-independent manner and is a selective ASIC1A strong receptor agonist. Baconguis et al. determined the eutectic structure of the ASIC1A and MitTx with minimal functional activity and captured the structure of the open state ASIC1A.
ASIC1A is a key subunit of ASICs and is widely expressed in the central and peripheral nervous systems. Deval et al found that ASIC1A is mainly distributed in the central cerebral cortex, hippocampus, cerebellum, pineal gland, amygdala, spinal cord and other parts. There is also ASIC1A expression in isolated human monocytes and differentiated osteoclasts, which are most abundantly expressed in human chondrocytes. RT-PCR and Western blot analysis showed that ASIC1A, ASIC2a, ASIC3 mRNA and protein were expressed in rat articular chondrocytes. Moreover, it is highly expressed in articular chondrocytes of adjuvant arthritis rats, in which ASIC1A expression level is significantly higher than other subunits. This suggests that ASIC1A may play a key role in the development of rheumatoid arthritis (RA) as a new target, which also provides a new way for the treatment of RA.
Chu et al. show that the pH for half-maximal activation (pH50) of the homopolymer ASIC1A channel is between 6.2 and 6.8. When the extracellular pH in the medium rapidly drops from 7.4 to a lower level, medium spiny neurons (MSNs) of the mouse striatum trigger transient inward currents. ASICs activation dose-response curves pH50 value is 6.25, which corresponds to pH50 value homomeric ASIC1A channel. At the same time, the ASICs current in MSNs has an inversion potential close to + 60 mV and a linear current-voltage relationship, indicating that the ASICs in the MSNs are Na+ selective.
ASIC1A with Rheumatoid Arthritis
Studies have shown that ASIC1A is expressed in human and rat articular cartilage and up-regulated in inflammatory states, suggesting that there is excessive activation of the ASIC1A channel in the course of RA. At present, the research on the role of ASIC1A in the mechanism of RA is mainly focused on the mechanism of apoptosis and autophagy.
In rat chondrocytes containing Ca2+ medium, extracellular acidification (pH 6.0) increases intracellular Ca2+ concentration ([Ca2+] i) and causes LDH release, resulting in chondrocyte death. The ASIC1A specific blocker PcTx-1 significantly reduced this increase in [Ca2+] i and inhibited acid-induced damage to rat articular chondrocytes. It is shown that the increase in [Ca2+] i may be mediated by ASIC1A. Further studies confirmed that ASIC1A and its protein expression were significantly reduced in small interfering RNA-mediated silencing models of ASIC1A expression in articular chondrocytes of AA rats, and the apoptosis rate and apoptosis level of articular chondrocytes were significantly reduced. At the same time, the expression of type II collagen and proteoglycan in articular chondrocytes increased significantly, suggesting that silencing ASIC1A can significantly inhibit the excessive apoptosis of articular chondrocytes in AA rats under the stimulation of extracellular acidification, and then play a protective role.
At the same time, it was found that amiloride can block ASICs and inhibit acid-induced chondrocyte apoptosis. The mechanism may be achieved by blocking ASICs from inhibiting Ca2+ overload, protecting mitochondrial function of chondrocytes, regulating the expression of Bcl-2 family of apoptotic genes, controlling the release of cyt-C and the activity of caspase apoptosis-executing proteins. Therefore, blocking ASIC1A-mediated Ca2+ overload and inhibiting excessive apoptosis of articular chondrocytes play a protective role, making ASIC1A a new potential target for the treatment of RA articular cartilage hyperinjury.
Zhang et al. confirmed that ASIC1A-mediated autophagy plays a key regulatory role in the development of RA. The autophagy level of rat articular chondrocytes cultured in vitro was significantly increased under the stimulation of extracellular acidification at pH 6.0, and the autophagosomes were significantly increased. The ASIC1A specific blocker PcTx-1 significantly inhibited the level of autophagy and decreased the number of autophagosomes. Further mechanistic studies revealed that the expression of autophagy-related gene Beclin-1 mRNA and autophagy protein LC3 was down-regulated after treatment with ERK1 / 2 phosphorylation inhibitor compared with pH 6.0, and the difference was statistically significant. This suggests that the extracellular acidification environment can induce the autophagy of articular cartilage. The inhibition mechanism of ASIC1A specific blocker PcTx-1 may be related to the inhibition of ERK1 /2 phosphorylation.
Figure 1. Proposed model for the role of AMPK/FoxO3a signaling in the ASIC1a-mediated autophagy in rat articular chondrocytes. (Dai, et al. 2017).
Our promise to you:
Guaranteed product quality, expert customer support.
Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.