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Regulatory Interdependence of Cloned Epithelial Na⁺ Channels and P2X Receptors

Scott S. Wildman^*, Joanne Marks^*, Linda J. Churchill^*, Claire M. Peppiatt, Ahmed Chraibi, David G. Shirley^*, Jean-Daniel Horisberger, Brian F. King^* and Robert J. Unwin^*

^* Department of Physiology and Centre for Nephrology, Royal Free and University College Medical School, University College London, London, United Kingdom; Department of Physiology, University College London, London, United Kingdom; Faculté de Medecine, Department de Physiologie et Biophysique, Université de Sherbrooke, Sherbrooke, Québec, Canada; and Institut de Pharmacologie et de Toxicologie, Université de Lausanne, Lausanne, Switzerland

Address correspondence to: Dr. Scott S. Wildman, Department of Physiology and Centre for Nephrology, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK. Phone: +44-0-207-794-0500 ext. 5204; Fax: +44-0-207-472-6476; E-mail:s.wildman{at}medsch.ucl.ac.uk

Received for publication February 2, 2005. Accepted for publication May 30, 2005.

Epithelial Na⁺ channels (ENaC) coexist with a family of ATP-gated ion channels known as P2X receptors in the renal collecting duct. Although ENaC is itself insensitive to extracellular ATP, tubular perfusion of ATP can modify the activity of ENaC. To investigate a possible regulatory relationship between P2X receptors and ENaC, coexpression studies were performed in Xenopus oocytes. ENaC generated a persistent inward Na⁺ current that was sensitive to the channel blocker amiloride (I_am-s). Exogenous ATP transiently activated all cloned isoforms of P2X receptors, which in some cases irreversibly inhibited I_am-s. The degree of inhibition depended on the P2X receptor subtype present. Activation of P2X₂, P2X_2/6, P2X₄, and P2X_4/6 receptor subtypes inhibited I_am-s, whereas activation of P2X₁, P2X₃, and P2X₅ receptors had no significant effect. The degree of inhibition of I_am-s correlated positively with the amount of ionic charge conducted by P2X receptor subtypes. ENaC inhibition required Na⁺ influx through I_am-s-inhibiting P2X ion channels but also Ca²⁺ influx through P2X₄ and P2X_4/6 ion channels. P2X-mediated inhibition of I_am-s was found to be due to retrieval of ENaC from the plasma membrane. Maximum amplitudes of ATP-evoked P2X-mediated currents (I_ATP) were significantly increased for P2X₂, P2X_2/6, and P2X₅ receptor subtypes after coexpression of ENaC. The increase in I_ATP was due to increased levels of plasma membrane–bound P2X receptor protein, suggesting that ENaC modulates protein trafficking. In summary, ENaC was downregulated by the activation of P2X₂, P2X_2/6, P2X₄, and P2X_4/6 receptors. Conversely, ENaC increased the plasma membrane expression of P2X₂, P2X_2/6, and P2X₅ receptors.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673