New Insights into G Protein-Coupled Receptor Signaling and Regulation


Scientific image from Benovic Paper

A collaborative study by the laboratories of Jeffrey L. Benovic, PhD,  in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University and the Sidney Kimmel Cancer Center at Jefferson, and Dr. Brian K. Kobilka in the Department of Molecular and Cellular Physiology at the Stanford University School of Medicine provides new insights into a general mechanism regulating signaling from G protein-coupled receptors (GPCRs). Two senior postdoctoral researchers, Dr. Konstantin E. Komolov of the Benovic lab and Dr. Yang Du of the Kobilka lab, share co-first authorship of the new study, which is published in the April 20th issue of Cell.

GPCRs play a central role in enabling cells to respond to extracellular stimuli, including various hormones, neurotransmitters, peptides, and proteins. Stimulation of the GPCR results in activation of G proteins, which in turn modulates the activity of downstream effectors that ultimately control numerous cellular functions, such as cell growth and motility. These signaling events are tightly regulated by two protein families, the GPCR kinases (GRKs) and the arrestins. GRKs bind to the ligand-occupied receptor and promote receptor phosphorylation, whereas arrestins bind to the phosphorylated receptor, deactivating G protein signaling and activating arrestin-mediated signaling. As Benovic explains, “GRKs play a central role in switching cells from G protein signaling to arrestin-mediated signaling, which is critical in maintaining normal cellular homeostasis.”

In the Cell study, the Benovic and Kobilka groups studied the interaction of a particular GPCR kinase, GRK5, with the b2-adrenergic receptor (b2AR), a GPCR that is activated by catecholamines such as adrenaline. Their findings reveal key mechanistic features of how these two proteins interact, and how this interaction leads to conformational changes in the GRK that are essential for mediating receptor phosphorylation. “The molecular model derived from these studies provides important insights into a common mechanism of GRK-GPCR interaction, raising the exciting possibility of exploiting this mechanism to control GPCR signaling,” adds Benovic.

The new findings hold promise for many clinical applications in the future. A naturally occurring amino acid polymorphism (Q41L) in GRK5 influences the GRK5-b2AR interaction, resulting in enhanced phosphorylation of the b2AR. This Q41L polymorphism is prevalent in African Americans and confers some protection against the development of congestive heart failure, illustrating the importance of understanding the physiological roles of GRK-GPCR interactions in human physiology and their varied effects across diverse human populations. Furthermore, GPCRs are the target of ~30% of drugs currently on the market, including drugs for the treatment of cancer, cardiovascular and airway disease, as well as various neurological and metabolic disorders. Because GRKs play a central role in regulating GPCR function, a better understanding of the mechanisms involved in this process provides an opportunity to manipulate this pathway in treating various diseases.

Future plans include dissecting further the interaction of GRK5 with b2AR using high-resolution structural and imaging approaches such as X-ray crystallography and cryo-electron microscopy, and also analyzing the dynamics of the interaction using approaches such as radiolytic footprinting and double electron electron resonance (DEER) spectroscopy. Studies are also envisioned to explore the broader significance of the newly reported results by examining other interacting pairs of GPCRs and GRKs. Commenting on the long-term goals of this project, Benovic notes that “understanding the structure of a GRK-GPCR complex should help us develop small molecules that enable us to either enhance or inhibit GRK regulation of the receptor, which should have tremendous implications for treating a wide variety of diseases.”

For further information: Konstantin E. Komolov, Yang Du, Nguyen Minh Duc, Robin M. Betz, João P. G. L. M. Rodrigues, Ryan D. Leib, Dhabaleswar Patra, Georgios Skiniotis, Christopher M. Adams, Ron O. Dror, Ka Young Chung, Brian K. Kobilka, and Jeffrey L. Benovic. 2017. Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5. Cell. In press.