The D(3) dopamine receptor is the major D(2)-like receptor that regulates sodium transport in the renal proximal tubule (RPT) and helps maintain blood pressure in the normal range. In Wistar-Kyoto (WKY) rats chronically fed high-salt diet, the intrarenal arterial infusion of a D(3) receptor agonist, PD128907, increased absolute and fractional sodium excretion. We have reported that Gα(12) and Gα(13), which participate in the signal transduction of the D(5) receptor, are expressed in RPTs. As the D(3) receptor is also expressed in RPTs, we hypothesized that it may also interact with Gα(12)/Gα(13) in RPTs from WKY rats. There were co-localization and co-immunoprecipitation of D(3) receptor and Gα(12)/Gα(13) in renal brush border membranes (BBMs) and RPT cells. The intrarenal infusion of PD128907 (1 μg kg(-1) min(-1)) that increased sodium excretion also increased the co-immunoprecipitations of D(3)/Gα(12) and D(3)/Gα(13) in renal BBMs; their co-immunoprecipitation was confirmed in RPT cells. As Gα(12) and Gα(13) increase sodium pump and transporter activity (for example, Na(+)-K(+)-ATPase, NHE3), an increased association of D(3) receptors with Gα(12)/Gα(13) receptors after D(3) receptor activation may be a mechanism to prevent Gα(12)/Gα(13)-mediated stimulation of sodium transport (and thus enhance natriuresis). We conclude that a D(3) receptor interaction with Gα(12)/Gα(13) that increases sodium excretion may have a role in the regulation of blood pressure.