Brain-specific regulator of G-protein signaling 9-2 selectively interacts with alpha-actinin-2 to regulate calcium-dependent inactivation of NMDA receptors.
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 alpha-actinin-2, suggesting a possible functional relationship between these proteins. Consistent with this idea, RGS9-2 and alpha-actinin-2 coimmunoprecipitated after coexpression in human embryonic kidney 293 (HEK-293) cells. Furthermore, endogenous RGS9-2 and alpha-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 alpha-actinin-2 could act in concert in central neurons. Like alpha-actinin-2, RGS9-2 coimmunoprecipitated NMDA receptors from striatal extracts, suggesting an interaction between RGS9-2, alpha-actinin-2, and NMDA receptors. Previous studies have shown that alpha-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 alpha-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 alpha-actinin-2 and suggest a potential novel role for RGS9-2 in the regulation of NMDA receptor function.
Mesh Terms:
Actinin, Adaptor Proteins, Signal Transducing, Animals, Blotting, Western, Calcium, Cell Line, Cloning, Molecular, Dopamine and cAMP-Regulated Phosphoprotein 32, Drug Interactions, Electric Stimulation, Gene Expression Regulation, Humans, Immunohistochemistry, Immunoprecipitation, Membrane Potentials, Membrane Proteins, N-Methylaspartate, Neural Inhibition, Patch-Clamp Techniques, Potassium, Potassium Channels, Prosencephalon, Protein Structure, Tertiary, Rats, Receptors, N-Methyl-D-Aspartate, Transfection, Two-Hybrid System Techniques
Actinin, Adaptor Proteins, Signal Transducing, Animals, Blotting, Western, Calcium, Cell Line, Cloning, Molecular, Dopamine and cAMP-Regulated Phosphoprotein 32, Drug Interactions, Electric Stimulation, Gene Expression Regulation, Humans, Immunohistochemistry, Immunoprecipitation, Membrane Potentials, Membrane Proteins, N-Methylaspartate, Neural Inhibition, Patch-Clamp Techniques, Potassium, Potassium Channels, Prosencephalon, Protein Structure, Tertiary, Rats, Receptors, N-Methyl-D-Aspartate, Transfection, Two-Hybrid System Techniques
J. Neurosci.
Date: Mar. 01, 2006
PubMed ID: 16510730
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