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

Abstract

Degenerative diseases often strike older adults and are characterized by progressive deterioration of cells, eventually leading to tissue and organ degeneration for which limited effective treatment options are currently available. Acid-sensing ion channels (ASICs), a family of extracellular H(+)-activated ligand-gated ion channels, play critical roles in physiological and pathological conditions. Aberrant activation of ASICs is reported to regulate cell apoptosis, differentiation and autophagy. Accumulating evidence has highlighted a dramatic increase and activation of ASICs in degenerative disorders, including multiple sclerosis, Parkinson's disease, Huntington's disease, intervertebral disc degeneration and arthritis. In this review, we have comprehensively discussed the critical roles of ASICs and their potential utility as therapeutic targets in degenerative diseases.

Keywords: acid-sensing ion channel (asic); calcium (ca2+); degenerative diseases; therapeutic target.

Figure 1.

The structure and electrophysiological properties of ASICs. (A) Structure of individual ASIC subunits. (B) Three subunits assemble to form a functional homo- or heterotrimeric channel. (C) Electrophysiological properties of ASICs: representative traces of ASIC1a, ASIC2a, and ASIC3 in pH 6.0, 4.5, and 5.0 solutions, respectively. The membrane potential was clamped to -60 mV.

Figure 2.

Roles of ASICs in arthritis fibroblast-like synoviocytes and chondrocytes. ASICs were activated by extracellular low pH to positively regulate [Ca²⁺]_i, inducing activation of PP2A and pERK to mediate cell death in FLS. Simultaneously, activated ASICs triggered intracellular Ca²⁺ accumulation in articular chondrocytes and subsequently upregulated Calpain, Calcineurin, Bax, Cytochrome c and Caspase 3/9, ultimately leading to chondrocyte apoptosis in arthritis.

Figure 3.

Schematic diagram summarizing the involvement of ASICs in cellular functions. Ischemia, inflammation and hypoxia give rise to tissue acidosis. ASICs are activated by extracellular H⁺ and mediate Ca²⁺ influx. [Ca²⁺]_i overload in various cell via ASICs leads to the development of degenerative diseases.