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Articles in PresS, published online ahead of print March 5, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00361.2001
Submitted on December 11, 2001
Accepted on February 25, 2002
1 Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, Houston, TX, USA
* To whom correspondence should be addressed. E-mail: MLokhandwala{at}uh.edu.
Dopamine (DA) and D1-like receptor agonists promote an increase in sodium excretion via activation of the D1-like receptor signaling cascade and subsequent inhibition of the Na,H-exchanger and the Na,K-ATPase in the renal proximal tubules. Recently, we have reported that DA and D1-like agonist failed to inhibit Na,K-ATPase activity in old Fischer 344 rats, due to uncoupling of D1A receptors from G-proteins, and this abnormality led to a diminished natriuretic response to DA in old Fischer 344 rats. In this study we have tested the hypothesis that the mechanism of this uncoupling may be an altered phosphorylation of D1A receptors in old rats. In experiments performed in renal cortical slices both DA and SKF 38393, a D1-like receptor agonist, increased the serine-phosphorylation of D1A receptors in adult (6-mo) but not old (24-mo) rats. Interestingly, the basal serine-phosphorylation of D1A receptors was higher in old than in adult rats. Competition ligand binding ([3H]-SCH 23390) experiments of D1-like receptor in adult and old rats with fenoldopam, a D1-like agonist, revealed the presence of two affinity states of the receptors. There was a rightward shift in the agonist displacement of the ligand in old compared to adult rats as reflected in the IC50 values (adult vs old, 7.46 x 10-9 ± 2.26 vs 7.93 x 10-7 ± 1.33 M). Also, there was a reduction for agonist affinity in the low affinity receptors in old than in adult rats (IC50, adult vs old, 5.67 x 10-5 ± 1.33 vs 12.60 x 10-5 ± 6.50 M). Moreover, the abundance of D1A receptor proteins was lower by an approximately 47% in the membranes of old compared to adult rats. We speculate that higher basal serine-phosphorylation of D1A receptors may have rendered D1A receptor uncoupled from G-protein leading to a reduced agonist affinity state and thus diminished natriuretic response to dopamine in old rats.
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