Extracellular fluid volume and to a certain extent blood pressure in mammals are determined by the balance between sodium intake and renal sodium excretion (1, 2). As regulator of sodium excretion, the intrarenal autocrine-paracrine dopamine (DA) 1 system assumes far greater importance than circulating endocrine or neurogenic dopamine (3-6). DA is produced in the proximal tubule via decarboxylation of its precursor L-dihydroxyphenylalanine derived from the plasma and glomerular filtrate (7-9) and is then secreted into the tubular lumen where it exerts its effects on multiple nephron segments, which cumulates in inhibition of tubular sodium absorption and natriuresis. Renal DA synthesis and excretion are increased by increased dietary salt and an intravenous saline load (10 -13), and blockade of DA synthesis or DA receptor significantly blunts the natriuretic response (14 -18). Quantitatively, the most significant inhibition of sodium transport occurs in the proximal tubule. DA inhibits proximal tubule sodium absorption partially by hemodynamic alterations (19 -22), but the major effect is directly on the tubule epithelium (23-26) via inhibition of two principal sodium transporters: the apical membrane Na ϩ /K ϩ exchanger (NHE3) (27-33) and the basolateral Na ϩ ,K ϩ -ATPase (34 -38). These effects are mediated by the DA receptor where five molecular isoforms (DR 1 -like receptors: DR 1 and DR 5 , and DR 2 -like receptors DR 2 , DR 3 , and DR 4 ) have been identified to date; all five isoforms are known to be present in the renal tubular epithelium (39 -43).Previous studies in isolated apical membrane vesicles have shown that DA inhibits proximal tubule apical membrane Na ϩ /H ϩ exchange activity mainly via DR 1 -like receptors (25-28, 30, 31, 33) through both PKA-dependent and PKA-independent mechanisms (27, 31). The Na ϩ /H ϩ exchanger on the apical membrane of the renal proximal tubule is encoded by NHE3 (44 -46), one of the seven members of the NHE gene family (47). We have shown in opossum kidney (OK) cells that the DA 1 -like and DA 2 -like receptors have synergistic actions on NHE3 activity and that inhibition of NHE3 activity by DA is accompanied by complex changes in NHE3 phosphorylation and dephosphorylation (33). However, the mechanisms by which DA acutely reduces NHE3 activity have not been examined. Redistribution of NHE3 transporters has been shown to mediate regulation of NHE3 activity in intact kidney (48 -54), in cultured renal epithelial cells (55,56), and in transfected fibroblasts (57-64). In addition, although NHE phosphorylation has been associated with changes in NHE3 activity (52,(65)(66)(67)(68), and phosphorylation appears to be functionally important for regulation of NHE3 activity by pharmacologic activators of protein kinases in transfected fibroblasts (65-67), the physiologic significance of NHE3 phosphorylation is still undetermined. In this paper we characterize one mechanism by which DA acutely inhibits NHE3: the internalization of NHE3 secondary to PKA-mediated NHE3 phosphorylatio...

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