Historical Perspective of the G Protein-Coupled Receptor Kinase Family.

Jeffrey L. Benovic

doi:10.3390/cells10030555

Abstract

Agonist activation of G protein-coupled receptors promotes sequential interaction of the receptor with heterotrimeric G proteins, G protein-coupled receptor kinases (GRKs), and arrestins. GRKs play a central role in mediating the switch from G protein to arrestin interaction and thereby control processes such as receptor desensitization and trafficking and arrestin-mediated signaling. In this review, I provide a historical perspective on some of the early studies that identified the family of GRKs with a primary focus on the non-visual GRKs. These studies included identification, purification, and cloning of the β-adrenergic receptor kinase in the mid- to late-1980s and subsequent cloning and characterization of additional members of the GRK family. This helped to lay the groundwork for ensuing work focused on understanding the structure and function of these important enzymes.

Highlights

G protein-coupled receptors (GPCRs) are the largest family of membrane-localized proteins in mammals and function to enable cells to transmit extracellular stimuli such as hormones, chemokines, ions, peptides, and sensory stimuli into intracellular functional changes [1]
While the studies described above highlight some of the initial work identifying the GPCR kinases (GRKs) family, we know much more about the role of GRKs in regulating GPCR function, a topic that has been extensively reviewed over the years [47,48,53,54,55,56,57,58]
What is left to do? We know a lot about GRKs and GRK activation from structural studies [59,60,61,62,63,64,65,66] and have some mechanistic insight on GRK-GPCR interaction [67,68]

Summary

Introduction

G protein-coupled receptors (GPCRs) are the largest family of membrane-localized proteins in mammals and function to enable cells to transmit extracellular stimuli such as hormones, chemokines, ions, peptides, and sensory stimuli into intracellular functional changes [1]. GPCRs primarily mediate their effects via the ability to interact in an activationdependent manner with three protein families: heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. Initial work by the Rodbell and Gilman laboratories led to the discovery of the heterotrimeric G proteins [2], whereas studies in retinal rod cells by several groups led to the initial discovery of GRKs and arrestins. I provide a historical overview of the initial discovery and characterization of the GRKs largely from my own personal perspective. This was the primary focus of my research in the Lefkowitz lab in the 1980s as well as a major focus of studies in my own laboratory starting in 1989

Discovery of Rhodopsin Kinase

The GRK Family

Role of GRKs in Desensitization

Summary