Regulator of G-Protein Signaling-2 as a Candidate Gene

Abstract

The “mosaic theory” of hypertension has been the prevailing dogma since its enunciation more than a half century ago. However, the ongoing search has been to determine which of the myriad of alterations in blood pressure regulatory systems occurs earliest in the process and are critical in the maintenance of the hypertensive state. Much of that focus has been directed to the determinants of increased peripheral resistance—perhaps the hallmark of the hypertensive state. The mechanisms underlying this abnormality reflect a combination of both structural and functional factors. From a functional perspective, peripheral resistance reflects a net balance between vasoconstrictor and vasodilator mechanisms. Defects in vasodilator mechanisms and enhancement of vasoconstrictor mechanisms have been described in human hypertension as well as in animal models. Central among these mechanisms have been alterations in G-protein-coupled receptor (GPCR) signaling pathways. Alterations in GPCR-signaling pathways in the hypertensive state are probably best explained by alterations downstream from the receptor. For those GPCRs linked to Gs and adenylyl cyclase activation, the impairment in GPCR/ G-protein “coupling” reflects both decreased G-protein function as well as the impact of increased expression/activity of the G-protein receptor kinases that interdict GPCR/G-protein signaling.1 For those mechanisms linked to vasoconstrictor process (via either Gi or Gq) the alterations also appear to be generalized across a range of receptors, consistent with a “downstream” effect.2 For …