Acid-sensing ion channels: trafficking and pathophysiology

Abstract

Acid-sensing ion channels (ASICs) are proton-gated cation channels that are widely expressed in both the peripheral and central nervous systems. ASICs contribute to a variety of pathophysiological conditions that involve tissue acidosis, such as ischemic stroke, epileptic seizures and multiple sclerosis. Although much progress has been made in researching the structure-function relationship and pharmacology of ASICs, little is known about the trafficking of ASICs and its contribution to ASIC function. The recent identification of the mechanism of membrane insertion and endocytosis of ASIC1a highlights the emerging role of ASIC trafficking in regulating its pathophysiological functions. In this review, we summarize the recent advances and discuss future directions on this topic.

Keywords: accessory proteins; acid-sensing ion channels; motifs; signaling pathways; surface expression; trafficking.

Figure 1.

Diagram of motifs within ASIC1a. The trafficking motifs in the extracellular loop and cytoplasmic domains are indicated. Tyr71 and Trp287 are involved in the TM1-thumb interaction. Asp107–Arg160 (linked by the line) is a conserved salt bridge. Asn393 is the N-glycosylation site. The blue characters indicate the phosphorylation sites, and red characters indicate motifs mentioned in the manuscript. The red characters at the C-terminus indicate the motifs that are critical for ASIC1a surface expression.

Figure 2.

Dynamic trafficking of ASIC1a. Left: activation of TrkB receptor by BDNF Facilitates the PI3K/Akt pathway, and then induces ASIC1a phosphorylation and forward targeting to the cell surface. Right: the endocytosis of ASIC1a is mediated by clathrin and dynamin-dependent processes.