Dopamine D1A receptor function is impaired in obesity-induced insulin resistance, contributing to sodium retention. We showed previously that uncoupling of D1A receptors from G proteins is responsible for diminished natriuretic response to dopamine in obese Zucker rats (OZRs). We hypothesized that overexpression of G protein-coupled receptor kinases (GRKs) leads to increased phosphorylation of D1A receptors, which in turn causes uncoupling of the receptors from GS proteins in proximal tubules of OZRs. We also examined effects of an insulin sensitizer, rosiglitazone, in correcting these defects. We found that basal and agonist (fenoldopam)-induced coupling of D1A receptors to GS proteins was impaired in proximal tubules of OZRs compared with lean Zucker rats (LZRs). Moreover, basal serine phosphorylation of D1A receptors was elevated two- to threefold in proximal tubules of OZRs compared with LZRs. Fenoldopam increased D1A receptor phosphorylation in proximal tubules of LZRs but not OZRs. Compared with that in LZRs, GRK4 expression in OZRs was elevated 200–300% in proximal tubule cell lysates and GRK2 expression was Ã30% higher in plasma membranes isolated from proximal tubules of OZRs. Rosiglitazone treatment restored basal and agonist-induced coupling of D1A receptors to GS proteins and reduced basal serine phosphorylation of D1A receptors, GRK4 expression, and translocation of GRK2 to the plasma membrane in proximal tubules of OZRs. Furthermore, rosiglitazone significantly reduced fasting blood glucose and plasma insulin in OZRs. Collectively, these results suggest that insulin resistance is responsible for GRK4 overexpression and GRK2 translocation leading to hyperphosphorylation of D1A receptors and their uncoupling from GS proteins as rosiglitazone treatment corrects these defects in OZRs. [ABSTRACT FROM AUTHOR]
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