TY - JOUR
AU - Jose,, P.A.
AB - Abstract The D1 receptor is important in blood pressure regulation because hypertension develops in D1 receptor knockout mice. A defect in the coupling of the D1 receptor to G-protein/effector complex in renal proximal tubules is also involved in the pathogenesis of spontaneous hypertension. Because we found no mutation of the D1 receptor gene in the spontaneously hypertensive rat (SHR), we tested the hypothesis that the uncoupling or desensitization of the D1 receptor is a result of increased receptor phosphorylation. Basal D1 receptor protein expression in renal cortex and renal proximal tubule cells was similar in Wistar-Kyoto (WKY) rats and SHRs. However, the amount of D1 receptor expressed in cell surface membranes was less in SHRs than in WKY rats. Moreover, basal serine-phosphorylated D1 receptor was greater in SHR (21±1 density units, DU) than in WKY rats (7±3 DU)(P<0.01); the D1 agonist, fenoldopam, increased serine-phosphorylated D1 receptor in WKY (55.0±2.8 DU) but not in SHRs (17±6 DU) (P<0.01) (n=5/group). The “hyper” phosphorylation of the D1 receptor in the SHR was not caused by homologous desensitization; similar results were obtained when dopamine synthesis was inhibited by carbidopa. Moreover, the decreased ability of D1 agonist to stimulate adenylyl cyclase and phospholipase C (n=5–8) and the basal “hyper” phosphorylation (n=3) of the D1 receptor was also observed in immortalized proximal tubular cells from SHRs (dopamine synthesis does not occur in the absence of DOPA, the substrate for renal dopamine synthesis). We next tested whether the increased phosphorylation of the D1 receptor in renal proximal tubules of SHR was caused by increased kinase or decreased phosphatase activity. In renal proximal tubules, basal protein phosphatase 2A (PP2A) activity and expression were similar in WKY and SHRs. However, fenoldopam increased PP2A activity and expression of the PP2A regulatory subunit, PP2A-B56, in WKY rats but not in SHRs. We conclude that increased serine-phosphorylation of the D1 receptor may cause the mislocation and the uncoupling of the D1 receptor from its G-protein/effector complex in renal proximal tubules of SHRs. This may be the result of a failure of resensitization caused by a defect in the regulatory subunit of PP2A. D1 receptor, phosphorylation, phosphatase activity This content is only available as a PDF. © 2000 by the American Journal of Hypertension, Ltd. American Journal of Hypertension, Ltd.
TI - Increased serine-phosphorylation of the D1 receptor in renal proximal tubule cells in spontaneous hypertension
JO - American Journal of Hypertension
DO - 10.1016/S0895-7061(00)00331-9
DA - 2000-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/increased-serine-phosphorylation-of-the-d1-receptor-in-renal-proximal-mqm5ucidx9
SP - 12A
EP - 13A
VL - 13
IS - S2
DP - DeepDyve
ER -