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Acid-sensing ion channels (ASICs) are neuronal receptors for extracellular protons. They contribute to the excitatory postsynaptic current and to the detection of painful acidosis. Moreover, they are activated during peripheral inflammation and acidosis associated with various neuronal disorders, such as stroke and neuroinflammation, rendering them interesting drug targets. Diminazene aceturate is a small-molecule inhibitor of ASICs with a reported apparent affinity in the low micromolar range, making it an interesting lead compound. It was reported that diminazene accelerates desensitization of ASICs, which was, however, not explained mechanistically. Furthermore, a binding site in a groove of the extracellular domain was proposed but not experimentally verified. In this study, we revisited the mechanism of inhibition by diminazene and its binding site on ASIC1a, the ASIC subunit with the greatest importance in the central nervous system. We show that diminazene slowly blocks ASIC1a, leading to the apparent acceleration of desensitization and underestimating its potency; we show that diminazene indeed has a submicromolar potency at ASIC1a (IC 50 0.3 μ M). Moreover, we show that the inhibition is voltage-dependent and competes with that by amiloride, a pore blocker of ASICs. Finally, we identify by molecular docking a binding site in the ion pore that we confirm by site-directed mutagenesis. In summary, our results show that diminazene blocks ASIC1a by a slow open-channel block and suggest that diminazene is an interesting lead compound for high-affinity blockers of ASICs.

Diminazene Is a Slow Pore Blocker of Acid-Sensing Ion Channel 1a (ASIC1a)