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Lookup NU author(s): Dr Francesca Di Sole
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The renal function of the A3 adenosine receptor (A3AR) is poorly characterized. In this study, we report that the A3AR-selective agonist, 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purine-9-yl]-1-deoxy-N-methyl-b- D-ribofuranuronamide (2-Cl-IBMECA) regulates the Na+/H+ exchanger-3 (NHE3) in a dose- and time-dependent fashion. In opossum kidney (OK) cells, 2-Cl-IBMECA at high (10-6 M) and low (10-8 M) dose inhibits NHE3 by a multiphasic time course with an acute phase of NHE3 inhibition from 15 min to 1 h, followed by a chronic phase of NHE3 inhibition from 24 to 48 h. Pre-incubation with either the selective A3AR-antagonist MRS1523 (10-7 M) or the protein kinase C inhibitor, Calphostin C (10-8 M) completely blocked 10-6 M 2-Cl-IBMECA-induced acute (15 min) and chronic (24 h) phases of NHE3 inhibition. In contrast, the acute inhibitory phase (15 min) of 10-8 M 2-Cl-IBMECA was completely prevented only when Calphostin C (10-8 M) was added in conjunction with the protein kinase A inhibitor, H89 (10-7 M). Acute (15 or 30 min depending on the A3AR-agonist concentration) A3AR-dependent inhibition of NHE3 activity was accompanied by decrease in cell surface NHE3 protein with no change in total NHE3 antigen. Chronic (24 h) A3AR-mediated down-regulation of NHE3 was associated with reduction of surface NHE3, decreased total NHE3 protein (70%) and a paradoxical rise of NHE3 RNA (40%). In summary, these results indicate that A3AR directly regulates NHE3 at multiple levels in a complex pattern. A3AR-dependent short- and long-term inhibition of NHE3 may be a fundamental mechanism of net sodium and fluid balance. © 2008 Wiley-Liss, Inc.
Author(s): Di Sole F, Cerull R, Babich V, Casavola V, Helmle-Roth C, Burckhardt G
Publication type: Article
Publication status: Published
Journal: Journal of Cellular Physiology
Year: 2008
Volume: 216
Issue: 1
Pages: 221-233
ISSN (print): 0021-9541
ISSN (electronic): 1097-4652
Publisher: John Wiley & Sons, Inc.
URL: http://dx.doi.org/10.1002/jcp.21399
DOI: 10.1002/jcp.21399
PubMed id: 18286509
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