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Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, Houston, Texas 77204
Dopamine (DA) and
D1-like receptor agonists promote an increase in Na
excretion by means of activation of the D1-like receptor signaling cascade and subsequent inhibition of the Na/H exchanger and
Na-K-ATPase in renal proximal tubules. Recently, our laboratory reported that DA and the D1-like receptor agonist failed to
inhibit Na-K-ATPase activity in old Fischer 344 rats because of
uncoupling of D1A receptors from G proteins and that 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 on the
D1-like receptor in adult and old rats with fenoldopam, a
D1-like receptor 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 with adult rats, as
reflected in the IC50 values (adult vs. old, 7.46 × 10
9 ± 2.26 vs. 7.93 × 107 ± 1.33 M). Also, there was a reduction in agonist affinity in the
low-affinity receptors in old compared with adult rats
(IC50, adult vs. old, 5.67 × 105 ± 1.33 vs. 12.60 × 105 ± 6.50 M). Moreover, the abundance of D1A receptor
proteins was ~47% lower in the membranes of old compared with adult
rats. We speculate that higher basal serine phosphorylation of
D1A receptors may have rendered the D1A
receptor uncoupled from G protein, leading to a reduced agonist
affinity state and thus diminished natriuretic response to DA in old rats.
dopamine; D1-like receptor agonist; D1A receptor; serine phosphorylation
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