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3 protein coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular epithelial cells is a PLC-PKC mediated event
1 Institute of Pharmacology & Therapeutics, Faculty of Medicine, Porto, Portugal
2 Pediatrics, Georgetown University Medical Center, Washington, DC, USA
* To whom correspondence should be addressed. E-mail: psoaresdasilva{at}netcabo.pt.
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 (SHR). 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 (CTX, 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-73,122, prevented the inhibitory effects of 7-OH-DPAT while PDBu and 7-OH-DPAT increased PLC activity and reduced NHE3 activity; down regulation of PKC abolished the inhibitory effects of both PDBu and 7-OH-DPAT on NHE activity. The inhibition of NHE3 activity by GTP
S and the prevention of the effect of 7-OH-DPAT by PTX suggest an involvement of an 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
3 antibody, but not in cells treated with antibodies against Gq/11, Gs, G
and Gi1,2 proteins. The calcium ionophore, A23187, 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 A23287 and thapsigargin. It is concluded that inhibition of NHE3 activity by dopamine D3 receptors coupled to Gi3 proteins is a PLC-PKC-mediated event, modulated by intracellular Ca2+.
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