Selective inhibition of α1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop

被引:86
作者
Hague, C [1 ]
Bernstein, LS [1 ]
Ramineni, S [1 ]
Chen, ZJ [1 ]
Minneman, KP [1 ]
Hepler, JR [1 ]
机构
[1] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA
关键词
D O I
10.1074/jbc.M502365200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:27289 / 27295
页数:7
相关论文
共 53 条
[1]   A comparison of aorta and vena cava medial message expression by cDNA array analysis identities a set of 68 consistently differentially expressed genes, all in aortic media [J].
Adams, LD ;
Geary, RL ;
McManus, B ;
Schwartz, SM .
CIRCULATION RESEARCH, 2000, 87 (07) :623-631
[2]  
Bell SE, 2001, J CELL SCI, V114, P2755
[3]   GAIP and RGS4 are GTPase-activating proteins for the G(i) subfamily of G protein alpha subunits [J].
Berman, DM ;
Wilkie, TM ;
Gilman, AG .
CELL, 1996, 86 (03) :445-452
[4]   RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11α signaling [J].
Bernstein, LS ;
Ramineni, S ;
Hague, C ;
Cladman, W ;
Chidiac, P ;
Levey, AI ;
Hepler, JR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (20) :21248-21256
[5]   RGS9-2 modulates D2 dopamine receptor-mediated Ca2+ channel inhibition in rat striatal cholinergic interneurons [J].
Cabrera-Vera, TM ;
Hernandez, S ;
Earls, LR ;
Medkova, M ;
Sundgren-Andersson, AK ;
Surmeier, DJ ;
Hamm, HE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (46) :16339-16344
[6]   Differences in the cellular localization and agonist-mediated internalization properties of the α1-adrenoceptor subtypes [J].
Chalothorn, D ;
McCune, DF ;
Edelmann, SE ;
García-Cazarín, ML ;
Tsujimoto, G ;
Piascik, MT .
MOLECULAR PHARMACOLOGY, 2002, 61 (05) :1008-1016
[7]   Cytoplasmic, nuclear, and Golgi localization of RGS proteins - Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs [J].
Chatterjee, TK ;
Fisher, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (31) :24013-24021
[8]   A seven-transmembrane RGS protein that modulates plant cell proliferation [J].
Chen, JG ;
Willard, FS ;
Huang, J ;
Liang, JS ;
Chasse, SA ;
Jones, AM ;
Siderovski, DP .
SCIENCE, 2003, 301 (5640) :1728-1731
[9]  
Cho H., 2004, Current Drug Targets - Immune Endocrine and Metabolic Disorders, V4, P107, DOI 10.2174/1568008043339938
[10]   The aorta and heart differentially express RGS (regulators of G-protein signalling) proteins that selectively regulate sphingosine 1-phosphate, angiotensin II and endothelin-1 signalling [J].
Cho, H ;
Harrison, K ;
Schwartz, O ;
Kehrl, JH .
BIOCHEMICAL JOURNAL, 2003, 371 :973-980