Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels

Location-Specific and Kinase-Independent GRK5 Function in Heart

“…It is very interesting to note that the functional outcome of GRK5 kinase-independent activity appears to be different from the outcomes observed in the GRK5 cardiac-specific knockout heart. Although the differences are consistent with distinct mechanisms for kinase-dependent versus kinase-independent activities of GRK5, we cannot exclude the potential impact from different strategies of genetic manipulation employed in these 2 studies, that is, global knockin 3 vs. cardiac specific knockout. 5 …”

“… 2 Understandably, these added complexities can significantly affect GRK-targeted therapeutic strategies, which largely focus on kinase inhibition and GRK-GPCR interactions. In this issue of JACC: Basic to Translational Science , a new report by Marzano et al 3 from the Koch and Cannavo labs provides an interesting and potentially important new insight to GRK5, a member of the GRK family, regarding its kinase-independent, and compartment-specific functions in the context of cardiac physiology and the pathogenesis of heart failure.…”

“…In their report, Marzano et al 3 aim to provide clear in vivo evidence to determine the kinase-independent functions of GRK5 in intact mice. 3 They used a CRISPR/Cas9-based precision genome editing approach to generate a new mouse line where the lysine (K) 215 residue of the mouse GRK5 protein, which is essential for its kinase activity, was replaced by an arginine (R). The mice carrying homozygous K215R mutant alleles showed the GRK5 mutant protein was expressed at normal levels but without its kinase activity.…”

“…The mice carrying homozygous K215R mutant alleles showed the GRK5 mutant protein was expressed at normal levels but without its kinase activity. Marzano et al 3 first characterized baseline cardiac function in the GRK5-K215R mice without any external stresses and found that these mice developed spontaneous contractile dysfunction associated with elevated apoptosis and fibrosis. Furthermore, GRK5-K215R mutant mice developed accelerated heart failure and cardiac remodeling on pressure-overload, but without affecting the induction of hypertrophy.…”

“…To further dissect the specific mechanisms involved in GRK5 kinase-independent activity in the heart, Marzano et al 3 performed more studies in cultured H9c2 cells, a cardiomyocyte cell line. First, they showed that excluding GRK5-kinase dead mutant from nuclei lowered p53 expression, while trapping the same GRK5 mutant inside of nuclei led to higher p53 expression and more cell death.…”