Deutsch
 
Benutzerhandbuch Datenschutzhinweis Impressum Kontakt
  DetailsucheBrowse

Datensatz

DATENSATZ AKTIONENEXPORT

Freigegeben

Zeitschriftenartikel

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

MPG-Autoren
/persons/resource/persons95249

Schupp,  Bettina
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons124409

Steigerwald,  Frank
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons93862

Kornau,  Hans Christian
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons93955

Köhr,  Georg
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

Volltexte (frei zugänglich)
Es sind keine frei zugänglichen Volltexte verfügbar
Ergänzendes Material (frei zugänglich)
Es sind keine frei zugänglichen Ergänzenden Materialien verfügbar
Zitation

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.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0029-3253-5
Zusammenfassung
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.