PICK1 regulates the trafficking of ASIC1a and acidotoxicity in a BAR domain lipid binding-dependent manner

Background: Acid-sensing ion channel 1a (ASIC1a) is the major ASIC subunit determining acid-activated currents in brain neurons. Recent studies show that ASIC1a play critical roles in acid-induced cell toxicity. While these studies raise the importance of ASIC1a in diseases, mechanisms for ASIC1a trafficking are not well understood. Interestingly, ASIC1a interacts with PICK1 (protein interacting with C-kinase 1), an intracellular protein that regulates trafficking of several membrane proteins. However, whether PICK1 regulates ASIC1a surface expression remains unknown. Results: Here, we show that PICK1 overexpression increases ASIC1a surface level. A BAR domain mutant of PICK1, which impairs its lipid binding capability, blocks this increase. Lipid binding of PICK1 is also required for PICK1-induced clustering of ASIC1a. Consistent with the effect on ASIC1a surface levels, PICK1 increases ASIC1a-mediated acidotoxicity and this effect requires both the PDZ and BAR domains of PICK1. Conclusions: Taken together, our results indicate that PICK1 regulates trafficking and function of ASIC1a in a lipid binding-dependent manner.