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J Biol Chem, Vol. 273, Issue 38, 24624-24632, September 18, 1998

Differential Coupling of ₁-, ₂-, and -Adrenergic Receptors to Mitogen-activated Protein Kinase Pathways and Differentiation in Transfected PC12 Cells

From the Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322

Three adrenergic receptor families that selectively activate three different G proteins (₁/G_q/11, ₂/G_i, and /G_s) were used to study mitogen-activated protein kinase (MAPK) activation and differentiation in PC12 cells. PC12 cells were stably transfected with _1A-, _2A-, or ₁-adrenergic receptors (ARs) in an inducible expression vector, and subclones were characterized. Norepinephrine stimulated inositol phosphate formation in _1A-transfected cells, inhibited cyclic adenosine 3'5'-monophosphate (cAMP) formation in _2A-transfected cells, and stimulated cAMP formation in ₁-transfected cells. Nerve growth factor activated extracellular signal-regulated kinases (ERKs) in all cell lines; however, norepinephrine activated ERKs only in _1A- and ₁-transfected cells but not in _2A-transfected cells. Norepinephrine also activated c-Jun NH₂-terminal kinase and p38 MAPK in _1A-transfected cells but not in ₁- or _2A-transfected cells. Norepinephrine caused differentiation of PC12 cells expressing _1A-ARs but not those expressing ₁- or _2A-ARs. However, norepinephrine acted synergistically with nerve growth factor in promoting differentiation of cells expressing ₁-ARs. Whereas ERKs are activated by G_i- but not G_s-linked receptors in many fibroblastic cell lines, we observed the opposite in PC12 cells. The results show that activation of the different G protein signaling pathways has different effects on MAPKs and differentiation in PC12 cells, with G_q signaling pathways activating all three major MAPK pathways.

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