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Am J Physiol Renal Physiol 287: F1059-F1066, 2004. First published July 20, 2004; doi:10.1152/ajprenal.00139.2004
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Gi{alpha}3 protein-coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event

Rui Pedrosa,1 Pedro Gomes,1 Ulrich Hopfer,2 Pedro A. Jose,3 and Patrício Soares-da-Silva1

1Institute of Pharmacology and Therapeutics, Faculty of Medicine, 4200-319 Porto, Portugal; 3Departments of Pediatrics and Physiology and Biophysics, Georgetown University Medical Center, Washington, District of Columbia 20007; and 2Department of Physiology, Case Western Reserve Medical School, Cleveland, Ohio 44106

Submitted 19 April 2004 ; accepted in final form 17 July 2004

This study evaluated the transduction pathway associated with type 3 Na+/H+ exchanger (NHE3) activity-induced inhibition during dopamine D3 receptor activation in immortalized renal proximal tubular epithelial cells from the spontaneously hypertensive rat. The dopamine D3 receptor agonist 7-OH-DPAT decreased NHE3 activity, which was prevented by the D2-like receptor antagonist S-sulpiride, pertussis toxin (PTX; overnight treatment), and the PKC inhibitor chelerythrine, but not by cholera toxin (overnight treatment), the MAPK inhibitor PD-098059, or the p38 inhibitor SB-203580. The PKA inhibitor H-89 abolished the inhibitory effects of forskolin on NHE3 activity, but not that of 7-OH-DPAT. The phospholipase C (PLC) inhibitor U-73122 prevented the inhibitory effects of 7-OH-DPAT, whereas PDBu and 7-OH-DPAT increased PLC activity and reduced NHE3 activity; downregulation of PKC abolished the inhibitory effects of both PDBu and 7-OH-DPAT on NHE activity. The inhibition of NHE3 activity by GTP{gamma}S and the prevention of the effect of 7-OH-DPAT by PTX suggest an involvement of a Gi/o protein coupled to the dopamine D3 receptor. Indeed, the 7-OH-DPAT-induced decrease in NHE3 activity was abolished in cells treated overnight with the anti-Gi{alpha}3 antibody, but not in cells treated with antibodies against Gq/11, Gs{alpha}, G{beta}, and Gi{alpha}1,2 proteins. The calcium ionophore A-23187 and the Ca2+-ATPase inhibitor thapsigargin increased intracellular Ca2+ but did not affect NHE3 activity. However, the inhibitory effects of PDBu and 7-OH-DPAT on NHE3 activity were completely abolished by A-23287 and thapsigargin. It is concluded that inhibition of NHE3 activity by dopamine D3 receptors coupled to Gi{alpha}3 proteins is a PLC-PKC-mediated event, modulated by intracellular Ca2+.

Na+/H+ exchange; protein kinases; hypertension


Address for reprint requests and other correspondence: P. Soares-da-Silva, Institute of Pharmacology and Therapeutics, Faculty of Medicine, 4200-319 Porto, Portugal (E-mail: psoaresdasilva{at}netcabo.pt)




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