Abstract
The RGSZ1 and RGSZ2 proteins, members of the RGS-Rz subfamily of GTPase-activating proteins (GAP), are involved in Mu-opioid receptor desensitization. The expression of these proteins, as well as of their main target the Gz protein, is virtually restricted to the nervous tissue. In synaptosomal membranes, these Rz proteins undergo post-translational modifications such as glycosylation and phosphorylation, and they may covalently attach to small ubiquitin-like modifier (SUMO) proteins. While RGSZ1 exists in conjugated and non-conjugated forms, RGSZ2 is mostly conjugated to SUMO-1, SUMO-2 and SUMO-3 proteins. These sumoylated forms of the GAPs readily associated with Mu-opioid receptors but they associated only poorly with Delta receptors. Furthermore, Gαi2 and Gαz subunits co-precipitated with the sumoylated forms of RGSZ1/Z2 proteins, but to a lesser extent with the Ser phosphorylated SUMO-free form of RGSZ1. Upon Mu-opioid receptor activation, there is a strong increase in the association of Gα proteins with RGSZ2 proteins that persists for intervals longer than 24 h. This effect probably accounts for their role in Mu-opioid receptor desensitization. Only a moderate increase was observed with RGSZ1, the non-sumoylated form of which probably acts as an efficient GAP for these Gα subunits. Therefore, sumoylation regulates the biological activity of RGS-Rz proteins and it is likely that it serves to switch their behavior, from that of a GAP for activated Gα subunits to that of a scaffold protein for specific signaling proteins.
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Acknowledgements
This work was supported by the grants SAF2003-01121 and SAF2005-01772. We are indebted to Dr Brigitte L Kieffer (University Louis Pasteur, Illkirch, France) for providing us with the C57BL/6 Mu-opioid receptor null (−/−) mice.
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Rodríguez-Muñoz, M., Bermúdez, D., Sánchez-Blázquez, P. et al. Sumoylated RGS-Rz Proteins Act as Scaffolds for Mu-Opioid Receptors and G-Protein Complexes in Mouse Brain. Neuropsychopharmacol 32, 842–850 (2007). https://doi.org/10.1038/sj.npp.1301184
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DOI: https://doi.org/10.1038/sj.npp.1301184
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