A Guanidinium Group Containing Dietary Supplement Inhibits ASIC3

Abstract

Acid‐sensing ion channels are sodium selective channels that are sensitive to extracellular protons, specifically those following ischemia and injury. The peripheral ASIC3 subtype plays an important role in pain perception. Protons and inflammatory mediators can activate or modulate ASIC3 to produce the pain signal, suggesting that ASIC3 is a pharmacological target for pain therapy. The large extracellular domain of ASICs offers multiple sites for interacting with protons and guanidinium group containing compounds. Guanidinium compounds such as 2‐guanidine‐4‐methylquinazoline (GMQ), amiloride, and agmatine are known to modulate the electrophysiological properties of ASIC3. Here we identified a dietary supplement (DS) that shares molecular similarity to these ASIC ligands and modulate ASICs. We utilize whole‐cell patch‐clamp electrophysiology recording to determine the interaction of DS with rat ASIC3 (rASIC3), transiently expressed in CHO‐K1 cells. Our preliminary data suggests that ASIC3 peak current amplitude and steady‐state current is reduced in the presence of DS. In the absence of extracellular calcium, DS reduces the rASIC3 proton sensitivity by shifting pH‐activation profile to lower pH. Future studies will focus on determining the effect of DS on the ASIC3 window current and other ASIC3 properties to resolve the mechanism of action of the DS influence on channel activity.