GABA-B1 Receptors are Coupled to the ERK1/2 MAP Kinase Pathway in the Absence of GABA-B2 Subunits

Abstract

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.

Activation of extracellular signal-regulated kinase signaling in the pedunculopontine tegmental cells is involved in the maintenance of sleep in rats

“…Additionally, the results of the present study show that activation of the ERK1/2-signaling pathway in PPT cells promotes both SWS and REM sleep by suppressing W. Thus, it appears that like in other cell types, in the PPT cells, PKA, CaMKII, and ERK1/2-signaling systems interact to regulate sleep-wake stages. On the basis of present findings and our previous studies as well as the studies of others (Datta et al 2001Datta and Siwek 2002;Vanhoose et al 2002;Paul et al 2003;Wetzker and Bohmer 2003;Ulloor et al 2004;Bandyopadhya et al 2006;Datta 2007;Tu et al 2007;Wang et al 2007Wang et al , 2007Richer et al 2009;Venkitaramani et al 2009;Datta and Desarnaud 2010;Stack et al 2010), we propose a working model for the signal transduction interactions in the PPT that lead to the regulation of sleepwake stages (Fig. 7).…”

“…2002; Wetzker and Bohmer 2003; Tu et al. 2007; Richer et al. 2009) and enhances down‐regulation of CaMKII and PKA‐signaling pathways (Datta 2007; Stack et al.…”

“…Earlier physiological and pharmacological studies have shown that the activation of GABA-B receptors on PPT cells increases SWS by suppressing W and REM sleep (Gauthier et al 1997;Ulloor et al 2004;Datta 2007). It is known that the activation of GABA-B receptors on many different cell types, including brain cells, increases phosphorylation and activation of the ERK1/2-signaling pathway (Vanhoose et al 2002;Wetzker and Bohmer 2003;Tu et al 2007;Richer et al 2009) and enhances down-regulation of CaMKII and PKA-signaling pathways (Datta 2007;Stack et al 2010). Thus, it is reasonable to suggest that, in the present study, during SWS, the increased expression, phosphorylation, and activation of ERK1/2 signaling in the PPT may have been caused by the activation of GABA-B receptors on the PPT cells.…”

GABAB Receptor Subunit GB1 at the Cell Surface Independently Activates ERK1/2 through IGF-1R Transactivation

“…It has been shown that intracellular GB1 alone induces ERK1/2 phosphorylation [26]. Here we compared the effect induced either by GB1 or GB1asa.…”

“…However, the temporal and spatial expression profiles of GB1 and GB2 do not always coincide [1], [3], [13], [18], suggesting that GB1 is functional in the absence of GB2. Furthermore, several lines of evidence suggest that GB1, independent of GB2, interacts with Kir3.1 channels [27], induces ERK1/2 phosphorylation and regulates leptin mRNA expression [26], [28]. However, all of these reports failed to detect obvious cell surface expression of GB1 in the absence of GB2.…”