Nephron specificity of dopamine receptor-adenylyl cyclase defect in spontaneous hypertension

Since DA1 receptors regulate renal tubular sodium transport, it is possible that the reported defect in the coupling between the DA1 dopamine receptor and adenylyl cyclase (AC) in the proximal tubule (PT) is a mechanism for the increased sodium reabsorption in animal models of spontaneous hypertension. Because the distal nephron may participate in the increased sodium retention in the spontaneously hypertensive rat (SHR), we determined whether the defective DA1 receptor-AC coupling described in PT of SHR is also present in the cortical collecting duct (CCD). Radioligand binding studies with the DA1 antagonist 125I-Sch 23982 revealed similar dissociation constants and maximum receptor densities in the CCD from Wistar-Kyoto rats (WKY) and SHR. Fenoldopam, a DA1-selective agonist, stimulated AC activity to a similar extent in CCD from both rat groups. Therefore the defective DA1 receptor-AC coupling in SHR has nephron segment specificity, since it is present in PT but not in CCD. One of the AC-linked dopamine receptors is an intronless D1A cloned from brain, which is also present in PT. Because the coupling defect in the PT may reside in the third cytoplasmic loop (involved in G protein coupling), we compared the sequence of this segment of the cloned D1A receptor using genomic DNA. Because no differences were noted between WKY and SHR, the coupling defect in the PT is not due to a mutation at the third cytoplasmic loop of the D1A receptor.