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1 Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, TX, USA
* To whom correspondence should be addressed. E-mail: Mlokhandwala{at}uh.edu.
Dopamine D1A receptor function is impaired in obesity-induced insulin resistance, contributing to sodium retention. We have previously shown that uncoupling of D1A receptors from G-proteins is responsible for diminished natriuretic response to dopamine in obese Zucker rats (OZRs). Here, we hypothesized that overexpression of GRKs leads to increased phosphorylation of D1A receptors, which in turn causes uncoupling of the receptors from Gs-proteins in proximal tubules of OZRs. In addition, we 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 were impaired in proximal tubules of OZRs compared to lean Zucker rats (LZRs). Moreover, basal serine-phosphorylation of D1A receptors was elevated by 2-3 fold in proximal tubules of OZRs compared to LZRs. Fenoldopam increased D1A receptor phosphorylation in proximal tubules of LZRs, but not OZRs. In comparison with LZRs, GRK4 expression was elevated 200-300% in proximal tubular cell lysates, and GRK2 expression was ~30% 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 overexpression of GRK4 and translocation of GRK2 leading to hyperphosphorylation of D1A receptors and their uncoupling from Gs-proteins as rosiglitazone treatment corrects these defects in OZRs.
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