Arrestins Come of Age: A Personal Historical Perspective - Progress in Molecular Biology and Translational Science - page 2

1. INTRODUCTION
For more than 40 years, I have had the privilege of watching and par-
ticipating in one of the most critical areas of biomedical research, that devoted
to understanding the nature, function, and regulation of the huge family of
G protein-coupled receptors (GPCRs). From my own point of view, much
of what we have learned about the activity and regulation of these receptors
relates to their ability to interact, in a stimulus-dependent fashion, with three
families of proteins: the heterotrimeric guanine nucleotide-binding proteins
(G proteins), for which they are named; the arrestins; and the G protein-
coupled receptor kinases (GRKs). This is not to deny the importance of other
families of proteins that, in turn, regulate the G proteins themselves (e.g.,
RGS) or numerous downstream signaling elements. However, the
G proteins, arrestins, and GRKs are the only proteins currently known which
interact almost universally with the stimulus- or agonist-modified receptors
and which are thus poised to most directly translate extracellular signals
impinging on the receptors into desired cellular perturbations.
The functions and activities of the arrestins andGRKs are inextricably inter-
related, and it is impossible to tell the story of one without the other. Most
remarkably, over the past 10-15 years, a major paradigm shift has occurred
in our understanding of how these families of proteins regulate and mediate
the activities of GPCRs. Both protein families were discovered in the context
of attempts to understand how the two prototypic GPCRs, rhodopsin and the
b 2-adrenergic receptor ( b 2AR), were desensitized, or turned off, after stimu-
lation. However, as this volume attests, this was just the beginning. Today, the
arrestins areknown to carryoutmultiple functions includingmediationofmyr-
iad signaling pathways as well as endocytic and trafficking functions, among
others.TheyhaveemergedasGPCRadaptor proteins par excellence, parlaying
their agonist-dependent association with the receptors into all manner of
downstream protein-protein interactions with important cellular conse-
quences. The reader will find all of these topics reviewed in this volume. Here,
I provide a very brief historical introduction to the field hanging the thread of
the story largely onwork frommy own laboratory over the past several decades.
2. “ PREHISTORY ” OF ARRESTINS
The protein we know today as arrestin (the visual arrestin, a.k.a.
arrestin1) was originally discovered in the 1970s as a highly immunogenic