HSP90 Regulation of P2X7 Receptor Function Requires an Intact Cytoplasmic C-Terminus

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...

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Bibliographic Details
Published in:Molecular pharmacology 2016-08, Vol.90 (2), p.116-126
Main Authors: Migita, Keisuke, Ozaki, Taku, Shimoyama, Shuji, Yamada, Junko, Nikaido, Yoshikazu, Furukawa, Tomonori, Shiba, Yuko, Egan, Terrance M., Ueno, Shinya
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - pharmacology
Animals
Benzoquinones - pharmacology
Cell Membrane - drug effects
Cell Membrane - metabolism
Cell Membrane Permeability - drug effects
Cytoplasm - metabolism
HEK293 Cells
HSP90 Heat-Shock Proteins - metabolism
Humans
Ion Channel Gating - drug effects
Lactams, Macrocyclic - pharmacology
Meglumine - metabolism
Mutant Proteins - metabolism
Protein Binding - drug effects
Protein Domains
Rats
Receptors, Purinergic P2X7 - chemistry
Receptors, Purinergic P2X7 - metabolism
Recombinant Proteins - metabolism
Structure-Activity Relationship
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Summary: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.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.115.102988