GABA-B(1) receptors are coupled to the ERK1/2 MAP kinase pathway in the absence of GABA-B(2) subunits.
In the current model of gamma-aminobutyric acid (GABA) B receptor function, there is a requirement for GABA-B(1/2) heterodimerisation for targetting to the cell surface. However, different lines of evidence suggest that the GABA-B(1) subunit can form a functional receptor in the absence of GABA-B(2). We observed coupling of endogenous GABA-B(1) receptors in the DI-TNC1 glial cell line to the ERK pathway in response to baclofen even though these cells do not express GABA-B(2). GABA-B(1A) receptors were also able to mediate a rapid, transient, and dose-dependent activation of the ERK1/2 MAP kinase pathway when transfected alone into HEK 293 cells. The response was abolished by G(i/o) and MEK inhibition, potentiated by inhibitors of phospholipase C and protein kinase C and did not involve PI-3-kinase activity. Finally, using bioluminescence resonance energy transfer and co-immunoprecipitation, we show the existence of homodimeric GABA-B(1A) receptors in transfected HEK293 cells. Altogether, our observations show that GABA-B(1A) receptors are able to activate the ERK1/2 pathway despite the absence of surface targetting partner GABA-B(2) in both HEK 293 cells and the DI-TNC1 cell line.
Richer
Maxime
M
Département de biochimie and Groupe de recherche universitaire sur le médicament (GRUM), Université de Montréal, Montréal, Québec, Canada.
David
Martin
M
Villeneuve
Louis R
LR
Trieu
Phan
P
Ethier
Nathalie
N
Pétrin
Darlaine
D
Mamarbachi
Aida M
AM
Hébert
Terence E
TE
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018682:GABA Agents / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D055503:Protein Multimerization; D051381:Rats; D018080:Receptors, GABA-B / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018682:GABA Agents; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D037342:Pertussis Toxin; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D001418:Baclofen