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The Journal of Neuroscience, March 1, 2006, 26(9):2522-2530; doi:10.1523/JNEUROSCI.4083-05.2006

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Cellular/Molecular
Brain-Specific Regulator of G-Protein Signaling 9-2 Selectively Interacts with -Actinin-2 to Regulate Calcium-Dependent Inactivation of NMDA Receptors

Mohamad Bouhamdan,^1,2 * Hai-Dun Yan,^1 * Xiu-Hua Yan,^1,2 Michael J. Bannon,^1,2,3 and Rodrigo Andrade^1,2

¹Department of Psychiatry and Behavioral Neurosciences, ²Department of Pharmacology, and ³Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48201

Correspondence should be addressed to Rodrigo Andrade, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 540 East Canfield, 2309 Scott Hall, Detroit, MI 48201. Email: randrade{at}med.wayne.edu

Regulator of G-protein signaling 9-1 (RGS9-1) and RGS9-2 are highly related RGS proteins with distinctive C termini arising from alternative splicing of RGS9 gene transcripts. RGS9-1 is expressed in photoreceptors where it functions as a regulator of transducin. In contrast, RGS9-2 is abundantly expressed in the brain, especially in basal ganglia, where its specific function remains poorly understood. To gain insight into the function of RGS9-2, we screened a human cDNA library for potential interacting proteins. This screen identified a strong interaction between RGS9-2 and -actinin-2, suggesting a possible functional relationship between these proteins. Consistent with this idea, RGS9-2 and -actinin-2 coimmunoprecipitated after coexpression in human embryonic kidney 293 (HEK-293) cells. Furthermore, endogenous RGS9-2 and -actinin-2 could also be coimmunoprecipitated from extracts of rat striatum, an area highly enriched in both these proteins. These results supported the idea that RGS9-2 and -actinin-2 could act in concert in central neurons. Like -actinin-2, RGS9-2 coimmunoprecipitated NMDA receptors from striatal extracts, suggesting an interaction between RGS9-2, -actinin-2, and NMDA receptors. Previous studies have shown that -actinin mediates calcium-dependent inactivation of NMDA receptors. In HEK-293 cells expressing NMDA receptors, expression of RGS9-2 significantly modulated this form of NMDA receptor inactivation. Furthermore, this modulation showed remarkable preference for NMDA receptor inactivation mediated by -actinin-2. Using a series of deletion constructs, we localized this effect to the RGS domain of the protein. These results identify an unexpected functional interaction between RGS9-2 and -actinin-2 and suggest a potential novel role for RGS9-2 in the regulation of NMDA receptor function.

Key words: RGS9; -actinin-2; NMDA receptors; striatum; calcium-dependent inactivation; protein–protein interactions; RGS9-2

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Received Sept. 26, 2005; revised Jan. 25, 2006; accepted Jan. 25, 2006.

Correspondence should be addressed to Rodrigo Andrade, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 540 East Canfield, 2309 Scott Hall, Detroit, MI 48201. Email: randrade{at}med.wayne.edu

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