Journal of Molecular Biology
Volume 366, Issue 2, 16 February 2007, Pages 349-365
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Review
How Regulators of G Protein Signaling Achieve Selective Regulation

https://doi.org/10.1016/j.jmb.2006.11.045Get rights and content

Abstract

The regulators of G protein signaling (RGS) are a family of cellular proteins that play an essential regulatory role in G protein-mediated signal transduction. There are multiple RGS subfamilies consisting of over 20 different RGS proteins. They are basically the guanosine triphosphatase (GTPase)-accelerating proteins that specifically interact with G protein α subunits. RGS proteins display remarkable selectivity and specificity in their regulation of receptors, ion channels, and other G protein-mediated physiological events. The molecular and cellular mechanisms underlying such selectivity are complex and cooperate at many different levels. Recent research data have provided strong evidence that the spatiotemporal-specific expression of RGS proteins and their target components, as well as the specific protein–protein recognition and interaction through their characteristic structural domains and functional motifs, are determinants for RGS selectivity and specificity. Other molecular mechanisms, such as alternative splicing and scaffold proteins, also significantly contribute to RGS selectivity. To pursue a thorough understanding of the mechanisms of RGS selective regulation will be of great significance for the advancement of our knowledge of molecular and cellular signal transduction.

Introduction

Upon binding to their specific receptors on the cell membranes, numerous neurotransmitters, hormones, growth factors, and drug chemicals selectively activate their own specific signaling pathways, accurately and precisely transduce the signals into cells and nuclei, and accomplish their activities and functions. The G protein-coupled receptors (GPCR) and the G protein-regulated ion channels represent a major class of signal transduction systems.1,2 It has now been well recognized that the regulators of G protein signaling (RGS) play essential regulatory roles in the G protein-mediated signal transduction.3

RGS proteins are a family of cellular proteins with conserved RGS domains (also called RGS box) of about 120 amino acid residues in length. RGS proteins specifically interact with the α subunits of G proteins, greatly enhance the intrinsic GTPase activities of Gα and accelerate the hydrolysis of GTP to GDP by Gα, thus converting G proteins from a GTP-bound active state to a GDP-bound inactive state and terminating G protein-mediated signaling.4

There are over 20 members in the mammalian RGS family. According to the similarity in sequence and features of structural domains, they have been classified into nine subfamilies (Table 1).4., 5., 6. We discuss mainly those that are directly involved in G protein-mediated signal transduction.

In animals and humans, there are hundreds of GPCRs and G protein-regulated ion channels. They are coupled to or regulated by different types of heterotrimeric G proteins that are coded by at least 20 different Gα, six different Gβ, and 11 different Gγ genes.7., 8., 9. Those G proteins are themselves regulated by multiple RGS proteins. It becomes obvious from these numbers that a specific RGS protein could be responsible for regulating several different types of G proteins, receptors, and ion channels. The reverse may also be true, that multiple RGS proteins could regulate a single type of G protein, receptor, or ion channel. Therefore, two fundamental questions raised here are: (1) do RGS proteins possess specificity and selectivity in their regulation of G protein-mediated signal transduction? (2) If RGS proteins do display specificity and selectivity, what are the molecular and cellular bases underlying such properties?

Biochemical and genetic knockout analyses have convincingly demonstrated that RGS proteins are essential regulatory elements in the G protein-mediated signal transduction pathways.10., 11., 12., 13., 14. Thus, it is of great significance and interest to address the two questions. Here, we review the recent advances in our understanding of the specificity and selectivity of RGS proteins. We first discuss experimental evidence that supports RGS selectivity, and then focus on specific molecular mechanisms.

Section snippets

RGS Proteins Display Specificity and Selectivity in their Interaction and Regulation

Since the first recognition of RGS proteins in yeast, invertebrates and vertebrates,10,15,16 great progress has been made in understanding the molecular structures, biochemical properties, and functions of this multigene family. Rich research data have demonstrated that RGS proteins possess specificity and selectivity in their regulation of G protein-mediated receptors, ion channels, and other signaling events. Basically, the data provide two kinds of evidence indicating RGS selectivity. One

Molecular and Cellular Bases of the Selectivity of RGS Proteins

The important question is: what are the molecular and cellular mechanisms by which RGS proteins achieve their specific interaction and selective regulation? Although we do not yet have a comprehensive knowledge and an integral explanation of how RGS proteins function selectively, recent advances in our understanding of the specific and selective interaction between some individual RGS proteins and their regulatory targets at the molecular and cellular levels has begun to provide answers to this

Conclusion

In vitro and in vivo studies have provided strong evidence that RGS proteins possess specificity and selectivity in their regulation of G protein-mediated signal transduction. In an analogy to the mechanisms of the selectivity of G proteins themselves, the molecular and cellular mechanisms underlying RGS selectivity are complex and coordinated at multiple levels. Besides the specific domains and sites within RGS proteins acting as molecular determinants, every molecular component that interacts

Acknowledgements

This work is supported by grant NS042593 from the National Institutes of Health.

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