No 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 by long-term whole-cell recording of CHO cells transfected with rASIC1a cDNA. Long but infrequent acidifications provided the same recovery time course as short acidifications of the same frequency. Steady-state desensitization is not related to the slow desensitization and attenuates the development of the slow desensitization. Consequently, 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 the slow desensitization. In summary, for influences of vastly different origin, including increase of calcium concentration, different pH conditions, and action of modulating drugs, we found a correlation between the effect on response amplitude and on development of slow desensitization. Thus, our results prove that a slow desensitization requires the open ion-permeable state.