Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 29, Pages 27289-27295Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M502365200
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Funding
- NIGMS NIH HHS [R01-GM61847] Funding Source: Medline
- NINDS NIH HHS [R01-NS37112] Funding Source: Medline
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Regulators of G-protein signaling (RGS) proteins act directly on G alpha subunits to increase the rate of GTP hydrolysis and to terminate signaling. However, the mechanisms involved in determining their specificities of action in cells remain unclear. Recent evidence has raised the possibility that RGS proteins may interact directly with G-protein-coupled receptors to modulate their activity. By using biochemical, fluorescent imaging, and functional approaches, we found that RGS2 binds directly and selectively to the third intracellular loop of the alpha(1A)-adrenergic receptor (AR) in vitro, and is recruited by the unstimulated alpha(1A)-AR to the plasma membrane in cells to inhibit receptor and G(q/11) signaling. This interaction was specific, because RGS2 did not interact with the highly homologous alpha(1B)- or alpha(1D)-ARs, and the closely related RGS16 did not interact with any alpha(1)-ARs. The N terminus of RGS2 was required for association with alpha(1A)-ARs and inhibition of signaling, and amino acids Lys(219), Ser(220), and Arg(238) within the alpha(1A)-AR i3 loop were found to be essential for this interaction. These findings demonstrate that certain RGS proteins can directly interact with preferred G-protein-coupled receptors to modulate their signaling with a high degree of specificity.
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