Hydrophobic Amines and Their Guanidine Analogues Modulate Activation and Desensitization of ASIC3

Abstract

Acid-sensing ion channel 3 (ASIC3) is an important member of the acid-sensing ion channels family, which is widely expressed in the peripheral nervous system and contributes to pain sensation. ASICs are targeted by various drugs and toxins. However, mechanisms and structural determinants of ligands’ action on ASIC3 are not completely understood. In the present work we studied ASIC3 modulation by a series of “hydrophobic monoamines” and their guanidine analogs, which were previously characterized to affect other ASIC channels via multiple mechanisms. Electrophysiological analysis of action via whole-cell patch clamp method was performed using rat ASIC3 expressed in Chinese hamster ovary (CHO) cells. We found that the compounds studied inhibited ASIC3 activation by inducing acidic shift of proton sensitivity and slowed channel desensitization, which was accompanied by a decrease of the equilibrium desensitization level. The total effect of the drugs on the sustained ASIC3-mediated currents was the sum of these opposite effects. It is demonstrated that drugs’ action on activation and desensitization differed in their structural requirements, kinetics of action, and concentration and state dependencies. Taken together, these findings suggest that effects on activation and desensitization are independent and are likely mediated by drugs binding to distinct sites in ASIC3.

Histidine Residues Are Responsible for Bidirectional Effects of Zinc on Acid-Sensing Ion Channel 1a/3 Heteromeric Channels

“…For example, recent studies have shown that homomeric ASIC1a was modulated by the alkaloid daurisoline isolated from the Chinese herb Menispermum dauricum [ 53 ]. ASIC3 channels were also modulated by endogenous isoquinoline alkaloids through reverse steady-state desensitization [ 54 ].…”

Ion Channels of Nociception

“…Shteinikov and co-workers [18] report the results of the experimental study on the action of the hydrophobic amines and their guanidine analogs on activation and desensitization of acid-sensing ion channels (ASIC). The ASIC3 subtype, studied here, with the highest acid sensitivity is primarily expressed in nociceptive neurons and likely implicated in various types of chronic and inflammatory pain associated with tissue acidosis.…”