Modulation of Slow Desensitization (Tachyphylaxis) of Acid-Sensing Ion Channel (ASIC)1a

Abstract

Among the proton-activated channels of the ASIC family, ASIC1a exhibits a specific tachyphylaxis phenomenon in the form of a progressive decrease in the response amplitude during a series of activations. This process is well known, but its mechanism is poorly understood. Here, we demonstrated a partial reversibility of this effect using long-term whole-cell recording of CHO cells transfected with rASIC1a cDNA. Thus, tachyphylaxis represents a slow desensitization of ASIC1a. Prolonged acidifications provided the same recovery from slow desensitization as short acidifications of the same frequency. Slow desensitization and steady-state desensitization are independent processes although the latter attenuates the development of the former. We found that drugs which facilitate ASIC1a activation (e.g., amitriptyline) cause an enhancement of slow desensitization, while inhibition of ASIC1a by 9-aminoacridine attenuates this process. Overall, for a broad variety of exposures, including increased calcium concentration, different pH conditions, and modulating drugs, we found a correlation between their effects on ASIC1a response amplitude and the development of slow desensitization. Thus, our results demonstrate that slow desensitization occurs only when ASIC1a is in the open state.

Keywords: Calcium dependence; Gating modulation; Tachyphylaxis; Voltage dependence; pH dependence.