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  Importance of the gamma-aminobutyric acid(B) receptor C-termini for G-protein coupling.

Grünewald, S., Schupp, B., Ikeda, S. R., Kuner, R., Steigerwald, F., Kornau, H. C., et al. (2002). Importance of the gamma-aminobutyric acid(B) receptor C-termini for G-protein coupling. Molecular Pharmacology, 61(5), 1070-1080. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11961124.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-3253-5 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-325B-6
Genre: Journal Article
Alternative Title : Importance of the gamma-aminobutyric acid(B) receptor C-termini for G-protein coupling.

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 Creators:
Grünewald, Sylvia, Author
Schupp, Bettina1, Author              
Ikeda, Stephen R., Author
Kuner, Rohini, Author
Steigerwald, Frank1, Author              
Kornau, Hans Christian1, Author              
Köhr, Georg1, Author              
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1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              

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 Abstract: Functional gamma-aminobutyric acid(B) (GABA(B)) receptors assemble from two subunits, GABA(B(1)) and GABA(B(2).) This heteromerization, which involves a C-terminal coiled-coil interaction, ensures efficient surface trafficking and agonist-dependent G-protein activation. In the present study, we took a closer look at the implications of the intracellular C termini of GABA(B(1)) and GABA(B(2)) for G-protein coupling. We generated a series of C-terminal mutants of GABA(B(1)) and GABA(B(2)) and tested them for physical interaction, surface trafficking, coupling to adenylyl cyclase, and G-protein-gated inwardly rectifying potassium channels in human embryonic kidney (HEK) 293 cells as well as on endogenous calcium channels in sympathetic neurons of the superior cervical ganglion (SCG). We found that the C-terminal interaction contributes only partly to the heterodimeric assembly of the subunits, indicating the presence of an additional interaction site. The described endoplasmic reticulum retention signal within the C terminus of GABA(B(1)) functioned only in the context of specific amino acids, which constitute part of the GABA(B(1)) coiled-coil sequence. This finding may provide a link between the retention signal and its shielding by the coiled coil of GABA(B(2).) In HEK293 cells, we observed that the two well-known GABA(B) receptor antagonists [S-(R*,R*)]-[3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl) phosphinic acid (CGP54626) and (+)-(2S)-5,5-dimethyl-2-morpholineacetic acid (SCH50911) CGP54626 and SCH50911 function as inverse agonists. The C termini of GABA(B(1)) and GABA(B(2)) strongly influenced agonist-independent G-protein coupling, although they were not necessary for agonist-dependent G-protein coupling. The C-terminal GABA(B) receptor mutants described here demonstrate that the active receptor conformation is stabilized by the coiled-coil interaction. Thus, the C-terminal conformation of the GABA(B) receptor may determine its constitutive activity, which could be a therapeutic target for inverse agonists.

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Language(s): eng - English
 Dates: 2001-11-092002-01-252002-05-012002-05-01
 Publication Status: Published in print
 Pages: 11
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 Table of Contents: -
 Rev. Type: Peer
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Title: Molecular Pharmacology
  Other : Mol. Pharmacol.
Source Genre: Journal
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Publ. Info: Bethesda, Md. : American Society for Pharmacology and Experimental Therapeutics
Pages: - Volume / Issue: 61 (5) Sequence Number: - Start / End Page: 1070 - 1080 Identifier: ISSN: 0026-895X
CoNE: https://pure.mpg.de/cone/journals/resource/954925426203