Effect of Gene Variants on Dopamine Receptor Natriuretic Responses
Status:
Unknown status
Trial end date:
2013-06-01
Target enrollment:
Participant gender:
Summary
Hypothesis to be tested: Dopamine D1-like receptor-induced natriuresis is impaired in humans
with G protein-related kinase 4 gene variants.
Our research group has discovered a D1 receptor/adenylyl cyclase coupling defect in renal
PTCs from subjects with essential hypertension. We have found increased GRK-4 activity in
renal PTCs in human essential hypertension due to activating variants of GRK-4, an effect
that was reproduced in a transfected cell model. Preventing the translation of GRK-4
normalized the coupling of the D1 receptor to adenylyl cyclase in hypertension. Gene variants
of GRK-4 cause a ligand-independent serine-phosphorylation of the D1 receptor, resulting in
its uncoupling from the G-protein/effector complex. The desensitization of the D1 receptor in
the renal PTC is hypothesized to be the cause of the compromised natriuretic effect of DA
that eventually leads to Na+ retention and hypertension. The primary objective of this
protocol is to demonstrate that natriuresis engendered by D1-like receptor activation with
fenoldopam is blunted in subjects with 3 or more SNPs of GRK-4 compared with responses in
subjects with 0-2 SNPs.