Membrane potential changes occurring upon acidification influence the binding of small-molecule inhibitors to ASIC1a.

Membrane potential changes occurring upon acidification influence the binding of small-molecule inhibitors to ASIC1a. Neuropharmacology. 2019 Feb 01;: Authors: Mazzocchi N, Grohovaz F, Taverna S, Menegon A Abstract Acid-sensing ion channels (ASICs) are proton-activated, sodium-permeable channels, highly expressed in both central and peripheral nervous systems. ASIC1a is the most abundant isoform in the central nervous system and is credited to be involved in several neurological disorders including stroke, multiple sclerosis, and epilepsy. Interestingly, the affinity of ASIC1a for two antagonists, diminazene and amiloride, has recently been proposed to be voltage sensitive. Based on this evidence, it is expected that the pharmacology of ASIC1cannot be properly characterized by single-cell voltage-clamp, an experimental condition in which membrane potential is maintained close to resting values. In particular, these measurements do not take into account the influence of the membrane potential depolarization induced by ASIC1a activation during acidosis or neuronal activity. We show here the voltage-dependence of some small molecules antagonists (diminazene, amiloride and a new patented drug from Merck), but not of Psalmotoxin 1, a peptide binding to regions other than the pore. We also demonstrate that the opening of ASIC1a induced by moderate acidosis determines a depolarization sufficient to change the affinity of small molecule anta...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research