Abstract
P2X7 receptors (P2X7Rs) are ATP-gated ion channels that display the unusual property of current facilitation during long applications of agonists. Here we show that facilitation disappears in chimeric P2X7Rs containing the C-terminus of the P2X2 receptor (P2X2R), and in a truncated P2X7R missing the cysteine-rich domain of the C-terminus. The chimeric and truncated receptors also show an apparent decreased permeability to N-methyl-d-glucamine+ (NMDG+). The effects of genetic modification of the C-terminus on NMDG+ permeability were mimicked by preapplication of the HSP90 antagonist geldanamycin to the wild-type receptor. Further, the geldanamycin decreased the shift in the reversal potential of the ATP-gated current measured under bi-ionic NMDG+/Na+ condition without affecting the ability of the long application of agonist to facilitate current amplitude. Taken together, the results suggest that HSP90 may be essential for stabilization and function of P2X7Rs through an action on the cysteine-rich domain of the cytoplasmic the C-terminus.
Footnotes
- Received December 14, 2016.
- Accepted June 10, 2016.
This work was supported by Grant-in-Aid for Scientific Research (C) [No. 26460693] and for Exploratory Research [No. 25670663] from the Japan Society for the Promotion of Science and by a Priority Research Grant for Young Scientists Designated by the President of Hirosaki University.
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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