ReviewRGS17/RGSZ2 and the RZ/A family of regulators of G-protein signaling
Section snippets
RGS proteins and G-protein signaling
G-protein coupled receptors (GPCRs) comprise a superfamily of cell surface, seven transmembrane-spanning proteins that mediate the physiological actions of a diverse group of stimuli including odorants, light, Ca2+, hormones, neurotransmitters, small peptides and proteins [1], [2]. GPCRs are functionally coupled to intracellular heterotrimeric guanine nucleotide binding proteins (G-proteins), which consist of Gα, Gβ and Gγ subunits. Activation of the receptor causes a conformational change that
RZ/A protein domains-modifications and localization
Although RZ/A proteins consist primarily of an RGS box, a number of post-translational modifications and interactions that may contribute to their function have been identified or postulated.
RZ/A protein interactions and signaling
There is increasing evidence that the cellular functions of RGS proteins (including RZ/A proteins) may extend beyond their GAP activities, and can involve interactions with receptors or intracellular signaling proteins (for review see Abramow-Newerly et al. [7]).
RZ/A-G-protein selectivity
As previously discussed, RGSZ1 was first isolated from bovine brain as a GAP for Gαz, and the RZ/A family was subsequently named after this activity. In spite of its relatively low sequence similarity (∼60% amino acid identity [63]), Gαz is considered to be a member of the Gαi/o family of G-proteins based upon this homology and its ability to inhibit adenylyl cyclase and stimulate K+ channels [64], [65]. However, it is not a typical Gαi/o protein, since it is insensitive to pertussis toxin and
Tissue and subcellular distribution of RZ/A proteins
In order to provide insight into RGS17 function in vivo, we examined the distribution of RGS17 mRNA in human tissues by Northern blot [13]. Our study showed that RGS17 is expressed in both human CNS and peripheral tissues, which is consistent with its GAP activity towards multiple Gα subtypes that are widely distributed in these tissues. Thus, RGS17 mRNA was expressed as a single ∼2 kb transcript at a low level in a variety of human peripheral tissues with higher levels in spleen, lung and blood
Conclusion
Although they have a conserved simple structure, RZ/A family proteins display an unexpected diversity in G-protein specificity, post-translational modification, subcellular localization, receptor selectivity, and tissue localization. Further studies are required to define their distinct roles and importance in vivo, and the mechanisms by which RZ/A proteins regulate G-protein-dependent and -independent signaling.
Acknowledgements
We thank Aya Goto for assistance with immunohistochemistry and Dr Chau Nguyen for his comments on the manuscript, and we acknowledge funding for studies of RGS proteins in our laboratories by Canadian Institutes of Health Research (CIHR) (to P.R.A. and P.C.) and Ontario Mental Health Foundation (P.R.A.). P.R.A. is the CIHR/Novartis Michael Smith Chair in Neurosciences and C.N. holds a Postdoctoral Fellowship from the CIHR.
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