Deactivation of vasodilator responses by GRK2 overexpression: a mechanism or the mechanism for hypertension?

In medicine, it is said that if a disease has many purported treatments, it generally means that there is no clear cure or ideal form of therapy. With regard to the disease primary hypertension—one of the leading causes of cardiovascular morbidity and mortality globally—an analogous statement can be made regarding its cellular pathophysiology: where many known pathophysiological defects are described, identification of the root cause(s) remains elusive. Among the cellular defects associated with the primary hypertension, the majority has been ascribed to alterations in the cell membrane. Alterations in function and expression of a range of membrane transporters, channels, and receptors have been reported and have been associated with the increase in vascular resistance, which is the hallmark of the disease. Perhaps the most studied of these membrane defects are those related to function of the G-protein coupled receptors (GPCRs)—especially those GPCRs expressed on endothelial and vascular smooth muscle cells regulating vasoconstriction and vasodilation. However, for many of these perturbations in GPCR function, it has been difficult to determine whether they are the cause or consequence of the disease. The article in this issue of Molecular Pharmacology by Eckhart et al. (2002) makes a useful contribution to our ability to determine the causal relationship between alterations in vascular GPCR function and the pathogenesis/maintenance of the hypertensive state. Probably the most consistently described vascular GPCRrelated defect in humans is impairment in response to activation of GPCRs linked to vasodilation via adenylyl cyclase activation (although enhanced activation of GPCRs linked to vasoconstriction has been reported in animal models of hypertension—e.g., 1 adrenergic receptors, 2 adrenergic receptors, and angiotensin receptors). The prototypes for these studies are those examining the impairment of -adrenergic responses. However, especially in animal models of hypertension, impaired vasodilator responses and impaired agonist-mediated adenylyl cyclase activation have been described for a range of hormones that activate other Gs-linked GPCRs, including dopamine, adenosine, glucagon, prostanoids, vasopressin, and parathormone (reviewed by Feldman and Gros, 1998). Defects in G-protein function have been described in human hypertension. This has primarily been in the context of impaired Gs function (Feldman et al., 1995; Feldman and Chorazyczewski, 1997), although enhanced Gi function has been reported in animal models of hypertension (Marcil et al., 1997). However, the predominant defect explaining the impairment in GPCR-stimulated adenylyl cyclase activity in hypertension seems to be a functional uncoupling of these GPCRs from Gs. The efficiency with which GPCRs interact with G-proteins is dependent, at least in part, on the phosphorylation state of the receptor. GPCR phosphorylation is mediated by at least two classes of serine-threonine kinases: the second messenger-dependent protein kinases (PKA, PKC) and members of the GPCR kinase family (GRKs). Increased GRK function has been described in both human and animal models of hypertension (Gros et al., 1997, 1999, 2000; Ishizaka et al. 1997). Furthermore, increased protein expression of a member of the GRK family (GRK2) has been implicated as the principal factor in the uncoupling of GPCR/G-protein in the hypertensive state—both in human hypertension (Gros et al. 1997, 1999) and in the spontaneously hypertensive rat model (Gros et al. 2000). In human hypertension, GRK2 expression is both inversely correlated with -adrenergic-stimulated adenylyl cyclase activity as well as positively correlated with blood pressure (Gros et al. 1997, 1999). However, as with the reports of other cellular defects described in hypertension, an association, not a causal relationThe studies from my laboratory referenced in this article were supported by grants from the Canadian Institutes of Health Research.