Chapter 6 Structure, Function, and Localization of Gβ5–RGS Complexes

Abstract

Members of the R7 subfamily of regulator of G protein signaling (RGS) proteins (RGS6, 7, 9, and 11) exist as heterodimers with the G protein beta subunit Gβ5. These protein complexes are only found in neurons and are defined by the presence of three domains: DEP/DHEX, Gβ5/GGL, and RGS. This article summarizes published work in the following areas: (1) the functional significance of structural organization of Gβ5–R7 complexes, (2) regional distribution of Gβ5–R7 in the nervous system and regulation of R7 family expression, (3) subcellular localization of Gβ5–R7 complexes, and (4) novel binding partners of Gβ5–R7 proteins. The review points out some contradictions between observations made by different research groups and highlights the importance of using alternative experimental approaches to obtain conclusive information about Gβ5–R7 function in vivo.

Inhibitory signaling by CB1 receptors in smooth muscle mediated by GRK5/β-arrestin activation of ERK1/2 and Src kinase

“…It is possible that interaction of G␤␥ with both CB 1 receptor and G␣ i allows for productive guanine nucleotide exchange on G␣ i without sustaining downstream signaling via G␤␥. Alternatively, the G␤␥ dimer could be atypical, consisting, for example, of G␤ 5 bound to the G␥-like domain of R7 subfamily of RGS proteins (e.g., RGS6, -7, -9, -11) (1,28). This subfamily is defined by the presence of three domains: an NH 2 -terminal DEP (Dishevelled, Egl, Pleckstrin) domain, linked via a DEP helical extension to a central G␥-like domain tightly bound to a COOH-terminal catalytic domain with selectivity for G␣ i .…”

“…This subfamily is defined by the presence of three domains: an NH 2 -terminal DEP (Dishevelled, Egl, Pleckstrin) domain, linked via a DEP helical extension to a central G␥-like domain tightly bound to a COOH-terminal catalytic domain with selectivity for G␣ i . Although these atypical G protein dimers are preferentially expressed in neural tissues (28), a member of this subfamily, G␤ 5 -RGS6, has also been found in smooth muscle (14). A G␤ 5 -RGS6 heterodimer could bind to G␣ i and permit CB 1 receptor-mediated nucleotide exchange without being able to substitute for, or signal in place of, a canonical G␤␥.…”

Regulator of G Protein Signaling 7 (RGS7) Can Exist in a Homo-oligomeric Form That Is Regulated by Gαo and R7-binding Protein

“…The C-terminally located RGS domain can act as a GAP for G i/o , but not for the G q family of G proteins (26 -30). The R7 RGS proteins regulate sensory transduction and locomotion and reward behavior and other processes via inhibition of dopaminergic, serotonergic, GABAergic, and opioidergic signaling (31)(32)(33). However, RGS7 can also regulate the G q -coupled M3 muscarinic receptor through a mechanism that is independent of the RGS domain (34 -37).…”

A Polymorphic Microdeletion in the RGS9 Gene Suppresses PTB Binding and Associates with Obesity

“…These studies provide a precedent for R7 RGS family proteins regulating body-weight through their expression in the brain since the protein products of the R7 RGS gene family have been reliably detected only in the brain or in excitable tissue such as retina and heart [5,9]. Further support for a role for R7 RGS proteins in regulating body weight and adiposity has been provided through studies with Gβ5, a unique G protein β subunit.…”

“…RGS9 protein is a member of the family of Regulators of G-Protein Signaling (RGS) proteins and expression of RGS9 is highly enriched in the striatum region of the brain [5][6][7][8][9]. Dopaminergic circuits in the striatum are activated by stimuli associated with reward and are also densely interconnected with the hypothalamus, a brain region that is critical for regulating energy expenditure [10].…”