A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure

Abstract

Abstractβ-adrenergic receptor (βAR) blockade is standard therapy for cardiac failure and ischemia. G-protein coupled receptor kinases (GRKs) desensitize βAR, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans (AA), substituting leucine (L) for glutamine (Q) at position 41. GRK5-L41 more effectively uncoupled isoproterenol-stimulated responses than GRK5-Q41 in transfected cells and transgenic mice, and like pharmacological βAR blockade, GRK5-L41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-L41 and β-blocker treatment on mortality outcome in independent cohorts of AA cardiac failure (P=0.036) and ischemia (P=0.023). In 375 prospectively followed AA heart failure subjects, GRK5-L41 was protective against death/cardiac transplant (single allele: RR=0.28, 95% CI=0.12-0.66; two alleles: RR=0.08, 95% CI=0.04-0.19; P=0.004). The gain-of-function GRK5-L41 polymorphism facilitates βAR desensitization during catecholamine excess, imparting "genetic β-blockade" and improving survival in heart failure.

The Future of Pharmacogenetics in the Treatment of Heart Failure

“…The main cardiac GRKs are GRK2 and GRK5, screening identified 4 relevant genetic variants in the GRK 5 gene, but none in GRK2 (20). The Gln 41 Leu SNP is the most studied variant in the GRK 5 gene, this SNP is represented in the GRK5 regulatory domain.…”

“…To account for this varying treatment response, firstly it is worth appreciating that the underlying HF aetiology has been shown to affect drug response in HF and beyond this, ethnicity, gender, body mass index, renal function are likely implicated (14)(15)(16). But genetic polymorphisms manipulating drug response may also account for these findings (17)(18)(19)(20)(21).…”

Race and Beta‐Blocker Survival Benefit in Patients With Heart Failure: An Investigation of Self‐Reported Race and Proportion of African Genetic Ancestry

“…Moreover, it is imperfectly linked to genetic ancestry, which could indicate biological bases for difference in therapeutic responses, both risks and benefits. There are significant data suggesting that genetic variation, specifically many variants that are correlated to ancestral population, may also impact beta‐blocker effectiveness or HF disease progression 18, 19, 20, 21. Unraveling the limitations of these past reports of racial disparities in beta‐blocker efficacy among HFrEF patients requires genetic ancestry data that can objectively and quantitatively assess ancestral background.…”

Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y 12 receptor

“…In relation to GRKs, which are established regulators of GPCR activity and traffic, both human GRK2 and GRK3 genes appear to lack genetic variation in their coding regions whilst GRK4 and GRK5 possess variations that have significant functional impacts (reviewed in A GRK5 variant (Leu41Gln), which displays an enhanced ability to promote agonistdependent β1 and β2 adrenoceptor desensitization and internalization, has been shown to be involved in accelerated termination of β-adrenoceptor-induced cardiac contractility, improved protection against cardiac β-adrenoceptor overstimulation, better response to β-blockers and improved survival in heart failure (75,76). Interestingly in GRK5, this polymorphism is adjacent to a calmodulin-binding domain (77) which, following calcium-calmodulin binding, is reported to inhibit GRK5 catalytic activity towards receptors.…”