Potentiation and Block of ASIC1a by Memantine
Acid-sensing ion channels (ASICs) are modulated by various classes of ligands, including the recently described hydrophobic monoamines, which inhibit and potentiate ASICs in a subunit-specific manner. In particular, memantine inhibits ASIC1a and potentiates ASIC2a homomers. The aim of the present work was to characterize action mechanism of memantine on recombinant ASIC1a expressed in CHO (Chinese hamster ovary) cells. We have demonstrated that effect of memantine on ASIC1a strongly depends on membrane voltage, conditioning pH value and application protocol. When applied simultaneously with activating acidification at hyperpolarized voltages, memantine caused the strongest inhibition. Surprisingly, application of memantine between ASIC1a activations at zero voltage caused significant potentiation. Analysis of the data suggests that memantine produces two separate effects, voltage-dependent open-channel block and shift of steady-state desensitization curve to more acidic values. Putative binding sites are discussed based on the computer docking of memantine to the acidic pocket and the pore region.
KeywordsASIC Memantine Channel block Mechanism of action Molecular modeling
The work is supported by Russian Science Foundation Grant 16-14-00122.
V.Y.S. and T.B.T performed experiments. V.S.K. performed modeling. D.B.T. designed the project and drafted the manuscript. All the authors discussed the results and commented the manuscript.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
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