G protein-coupled receptor kinases: Past, present and future.

This review is provided in recognition of the extensive contributions of Dr. Robert J. Lefkowitz to the G protein-coupled receptor (GPCR) field and to celebrate his 75th birthday. Since one of the authors trained with Bob in the 80s, we provide a history of work done in the Lefkowitz lab during the 80s that focused on dissecting the mechanisms that regulate GPCR signaling, with a particular emphasis on the GPCR kinases (GRKs). In addition, we highlight structure/function characteristics of GRK interaction with GPCRs as well as a review of two recent reports that provide a molecular model for GRK-GPCR interaction. Finally, we offer our perspective on some future studies that we believe will drive this field.

Arrestins come of age: a personal historical perspective.

Visual arrestin and the two ß-arrestins (1 and 2) were originally discovered 25-30 years ago in the context of their ability to desensitize phosphorylated G protein-coupled receptors (rhodopsin and the ß2-adrenergic receptor, respectively). A fourth retinal-specific member of the family (X-arrestin) was discovered later. Over the past 10-15 years, however, it has become clear that these versatile molecules subserve a host of other roles in modulating and mediating the function of most GPCRs as well as other types of receptors. Functioning as multifunctional adaptor proteins, the ß-arrestins also play prominent roles in receptor endocytosis, signaling, trafficking, and ubiquitination among others. Here, I provide a brief personal perspective on how the field has evolved since its inception and speculate on future directions.

[Advances in the investigation of structure and function of G protein-coupled receptors (by awarding the Nobel Prize for Chemistry in 2012 to Robert Lefkowitz and Bryan Kobilka)].

The Nobel Prize for Chemistry in 2012 was awarded to Robert Lefkowitz and Bryan Kobilka "for studies in G-protein-coupled receptors" (GPCR). In this review the most important discoveries of these Nobel Prize winners dealing with investigation of the structure and functions of GPCR were discussed and analyzed. In the 1980s, they were the first in the world to clone GPCR--the 32-adrenergic receptor. After 20 years, the team led by B. Kobilka for the first time prepared this receptor in the crystalline form and established its three-dimensional structure. In these studies, unique approaches for purification and crystallization of other receptors were developed. In 1980s, R. Lefkowitz and his colleagues discovered beta-arrestins that regulate signal transduction occurring via GPCR. Later they revealed that beta-arrestins were the most important members of signal transduction and were responsible for the signal transduction from the hormone-activated receptor to intracellular signaling cascades independently of heterotrimeric G-proteins. These and other outstanding discoveries of R. Lefkowitz and B. Kobilka have become the basis for the novel area of molecular biology and pharmacology--the molecular endocrinology of GPCR.