Novel roles for G protein-coupled receptor kinases in cardiac injury and repair

G protein-coupled receptors (GPCRs) are key modulators of cell signaling. Multiple GPCRs are present in the heart where they regulate cardiac homeostasis including processes such as myocyte contraction, heart rate and coronary blood flow. GPCRs are pharmacological targets for several cardiovascular disorders including heart failure (HF) such as beta-adrenergic receptor (beta AR) blockers and angiotensin II receptor (AT1R) antagonists. The activity of GPCRs are finely regulated by GPCR kinases (GRKs), which phosphorylate agonist-occupied receptors and start the process of desensitization. Among the seven members of the GRK family, GRK2 and GRK5 are predominantly expressed in the heart, where they exhibit both canonical and non-canonical functions. Both kinases are known to be increased in cardiac pathologies and contribute to pathogenesis through their roles in different cellular compartments. Lowering or inhibiting their actions mediate cardioprotective effects against pathological cardiac growth and failing heart. Therefore, given their importance in cardiac dysfunction, these kinases are drawing attention as promising targets for the treatment of HF, which needs improved therapies. Over the past three decades, broad knowledge on GRK inhibition in HF has been gained by studies using genetically engineered animal models or through gene therapy with peptide inhibitors or using small molecule inhibitors. In this mini review, we summarize the work focusing on GRK2 and GRK5 but also discuss a couple of the non-abundant cardiac subtypes and their multi-functional roles in the normal and diseased heart and the potential and therapeutic targets.

Automated summary

G protein-coupled receptors (GPCRs) play a crucial role in cell signaling, including heart functions such as myocyte contraction and coronary blood flow regulation. GPCRs are important drug targets for cardiovascular disorders, and their activity is regulated by GPCR kinases (GRKs). GRK2 and GRK5 are primarily expressed in the heart and contribute to cardiac pathology. Inhibiting the actions of these kinases can provide cardioprotective effects against cardiac dysfunction. The inhibition of GRKs has been extensively studied in heart failure, and this review summarizes the research focusing on GRK2 and GRK5, as well as other cardiac subtypes and their roles in heart disease.