The GABA_B positive allosteric modulators CGP7930 and GS39783 stimulate ERK1/2 signalling in cells lacking functional GABA_B receptors

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• 作者：Maria C. Olianas ; ^{molianas@unica.it} ; Simona Dedoni ; Pierluigi Onali
• 关键词：CGP7930 (PubChem CID ; 5024764) ; GS39783 (PubChem CID ; 6604928) ; (-)-baclofen (PubChem CID ; 44602) ; SKF97541 (PubChem CID ; 5230) ; CGP55845 (PubChem CID ; 5311042) ; CGP54626 (PubChem CID ; 197584) ; phorbol 12-myristate 13 acetate (PubChem CID ; 27924) ; Go 6850 (PubChem CID ; 2396) ; 5Z-7-oxozeaenol (PubChem CID ; 9863776) ; GW5074 (PubChem CID ; 5924208)
• 刊名：European Journal of Pharmacology
• 出版年：2017
• 出版时间：5 January 2017
• 年：2017
• 卷：794
• 期：Complete
• 页码：135-146
• 全文大小：2300 K
• 卷排序：794

文摘

The present study shows that the GABAB positive allosteric modulators (PAMs) CGP7930 and GS39783 stimulate extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signalling in cells that do not express functional GABAB receptors. In human SH-SY5Y neuroblastoma cells, CGP7930 and GS39783 induced a time- and concentration-dependent increase in ERK1/2 phosphorylation with potencies similar to those displayed as GABAB PAMs. Conversely, γ-aminobutyric acid and the GABAB receptor agonists (-)baclofen and SKF97541 were completely inactive. CGP7930 and GS39783 enhanced the nuclear localization of phospho-ERK1/2 and CGP7930 promoted the phosphorylation of the transcription factors Elk-1 and CREB. CGP7930-induced ERK1/2 stimulation was insensitive to pertussis toxin, the Gq/11 antagonist YM254890 and the phospholipase C-β inhibitor U-73122, but was completely blocked by the MEK1/2 inhibitor PD98059. Inhibition of insulin-like growth factor-1, platelet--derived growth factor, phosphoinositide 3-kinase and Akt activities potentiated CGP7930-induced ERK1/2 phosphorylation. CGP7930 enhanced the phosphorylation of myristoylated alanine-rich protein kinase C (PKC) substrate and inhibition of PKC attenuated the ERK1/2 stimulation. Over-expression of N17Ras, a dominant negative mutant of c-Ras, or inhibition of c-Raf by GW5074 partially antagonized CGP7930-induced ERK1/2 activation. CGP7930 enhanced the phosphorylation of transforming growth factor-β-activated kinase 1 (TAK-1) and TAK-1 inhibition by 5Z-7-oxozeaenol reduced CGP7930-induced ERK1/2 phosphorylation. CGP7930 activated ERK1/2 in CHO-K1 fibroblasts, which lack endogenous GABAB receptors, but not in HEK-293 cells, indicating that the response displayed cell type specificity. These data demonstrate that CGP7930 and GS39783 can trigger ERK1/2 signalling, a critical modulator of mood and drug addiction, independently of an action on GABAB receptors.