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Basolateral P2X₄-like receptors regulate the extracellular ATP-stimulated epithelial Na⁺ channel activity in renal epithelia

¹Division of Medicine and ²National Heart and Lung Institute, Imperial College London, London; ³Department of Chemistry, Cambridge University, Cambridge; and ⁴The Office of the Vice Chancellor and ⁵The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom

Submitted 26 September 2006 ; accepted in final form 9 March 2007

Extracellular ATP initiates potent effects on sodium transport across renal epithelia through membrane-associated purinergic receptors. Dependent on the location of these receptors, ATP either inhibits or stimulates sodium reabsorption. Using A6 cells, transepithelial electrical resistance measurements, and scanning ion conductance microscopy, we have identified the purinergic receptors involved in the stimulatory action on the epithelial cell basolateral plasma membrane. Addition of the potent P2X₄ receptor agonist 2-methylthio-ATP (2MeSATP) to the basolateral side of the A6 monolayer stimulated amiloride-sensitive sodium conductance and produced similar cell morphological changes to those found with ATPS, aldosterone, or hypotonic stress. The agonist potency order determined by sodium conductance changes of the monolayer was: 2MeSATP ATPS > CTP, a similar agonist potency profile to that of cloned P2X₄ receptors but with higher sensitivity for , -methylene-ATP and ,-methylene-ATP. We further demonstrated that the ATP effect on sodium transport was potentiated by ivermectin, not blocked by suramin and PPADS, enhanced by Zn²⁺ but not by Cu²⁺, and significantly reduced but not totally inhibited by brilliant blue G. These results led us to conclude that basolateral P2X₄-like receptors were involved. We suggest that there is a reciprocal purinergic system acting both at a basolateral and apical location for control of Na⁺ transport. This requires a mechanism within the cell that leads to either basolateral or apical ATP release to regulate renal tubular function.

ENaC; scanning probe microscopy; scanning ion conductance microscopy; aldosterone; transepithelial electrical resistance

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