Our group has discovered a D1 receptor/adenylyl cyclase coupling defect in renal PTCs from subjects with essential hypertension. We have found increased GRK 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. The 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 may be the cause of the compromised natriuretic effect of DA that eventually leads to Na+ retention and hypertension. Therefore, a primary objective of the entire Program Project Grant, of which this protocol is one part, is to identify humans with salt-sensitive hypertension and resistance to the inhibitory effect of D1-like receptor agonist fenoldopam on renal proximal Na+ reabsorption and determine whether these individuals have the activating polymorphisms of GRK-4 alone or in combination with polymorphisms of genes of the RAS.