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Int. J. Mol. Sci. 2018, 19(4), 1161;

Opposing Roles of Calcium and Intracellular ATP on Gating of the Purinergic P2X2 Receptor Channel

Section on Cellular Signaling, National Institutes of Child Health and Human Development, NIH, Bethesda, MD 20892, USA
Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo 1781421, Chile
Laboratory of Developmental Physiology, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, Concepción 4030000, Chile
Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile
Centro para el Desarrollo de Nanociencias y Nanotecnología (CEDENNA), Santiago 9170022, Chile
Author to whom correspondence should be addressed.
Deceased on March 2017.
Received: 6 March 2018 / Revised: 30 March 2018 / Accepted: 3 April 2018 / Published: 11 April 2018
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases)
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P2X2 receptors (P2X2R) exhibit a slow desensitization during the initial ATP application and a progressive, calcium-dependent increase in rates of desensitization during repetitive stimulation. This pattern is observed in whole-cell recordings from cells expressing recombinant and native P2X2R. However, desensitization is not observed in perforated-patched cells and in two-electrode voltage clamped oocytes. Addition of ATP, but not ATPγS or GTP, in the pipette solution also abolishes progressive desensitization, whereas intracellular injection of apyrase facilitates receptor desensitization. Experiments with injection of alkaline phosphatase or addition of staurosporine and ATP in the intracellular solution suggest a role for a phosphorylation-dephosphorylation in receptor desensitization. Mutation of residues that are potential phosphorylation sites identified a critical role of the S363 residue in the intracellular ATP action. These findings indicate that intracellular calcium and ATP have opposing effects on P2X2R gating: calcium allosterically facilitates receptor desensitization and ATP covalently prevents the action of calcium. Single cell measurements further revealed that intracellular calcium stays elevated after washout in P2X2R-expressing cells and the blockade of mitochondrial sodium/calcium exchanger lowers calcium concentrations during washout periods to basal levels, suggesting a role of mitochondria in this process. Therefore, the metabolic state of the cell can influence P2X2R gating. View Full-Text
Keywords: purinergic receptor channels; desensitization; ATP; calcium; allosteric; covalent purinergic receptor channels; desensitization; ATP; calcium; allosteric; covalent

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Rokic, M.B.; Castro, P.; Leiva-Salcedo, E.; Tomic, M.; Stojilkovic, S.S.; Coddou, C. Opposing Roles of Calcium and Intracellular ATP on Gating of the Purinergic P2X2 Receptor Channel. Int. J. Mol. Sci. 2018, 19, 1161.

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