Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling.
G protein-coupled receptor kinases (GRKs) are classically known for their role in regulating the activity of the largest known class of membrane receptors, which influence diverse biological processes in every cell type in the human body. As researchers have tried to uncover how this family of kinases, containing only 7 members, achieves selective and coordinated control of receptors, they have uncovered a growing number of noncanonical activities for these kinases. These activities include phosphorylation of nonreceptor targets and kinase-independent molecular interactions. In particular, GRK2, GRK3, and GRK5 are the predominant members expressed in the heart. Their canonical and noncanonical actions within cardiac and other tissues have significant implications for cardiovascular function in healthy animals and for the development and progression of disease. This review summarizes what is currently known regarding the activity of these kinases, and particularly the role of GRK2 and GRK5 in the molecular alterations that occur during heart failure. This review further highlights areas of GRK regulation that remain poorly understood and how they may represent novel targets for therapeutic development.
*Department of Pharmacology, Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA; and †Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.
Sarah M
SM
Schumacher
Walter J
WJ
Koch
D000818:Animals; D002318:Cardiovascular Diseases / Q000201:enzymology* / Q000473:pathology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000502:physiology; D054768:G-Protein-Coupled Receptor Kinases / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*
C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; C517898:GRK5 protein, human