DIFFERENTIAL COUPLING OF ALPHA(1)-ADRENERGIC, ALPHA(2)-ADRENERGIC, AND BETA-ADRENERGIC RECEPTORS TO MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAYS AND DIFFERENTIATION IN TRANSFECTED PC12 CELLS

Three adrenergic receptor families that selectively activate three dif ferent G proteins (alpha(1)/G(q/11), alpha(2)/G(i), and beta/G(s)) wer e used to study mitogen-activated protein kinase (MAPK) activation and differentiation in PC12 cells. PC12 cells were stably transfected wit h alpha(1a)-, alpha(2A)-, or beta(1)-adrenerse receptors (ARs) in an i nducible expression vector, and subclones were characterized. Norepine phrine stimulated inositol phosphate formation in alpha(1A)-transfecte d cells, inhibited cyclic adenosine 3'5'-monophosphate (cAMP) formatio n in alpha(1A)-transfected cells, and stimulated cAMP formation in bet a(1)-transfected cells. Nerve growth factor activated extracellular si gnal-regulated kinases (ERKs) in all cell lines; however, norepinephri ne activated ERKs only in alpha(1A)- and beta(1)-transfected cells but not in alpha(2A)-transfected cells. Norepinephrine also activated c-J un NH2-terminal kinase and p38 MAPK in alpha(1A)-transfected cells but not in beta(1)- or alpha(2A)-transfected cells. Norepinephrine caused differentiation of PC12 cells expressing alpha(1A)-ARs but not those expressing beta(1)- or alpha(2A)-ARs. However, norepinephrine acted sy nergitically with nerve growth factor in promoting differentiation of cells expressing beta(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 d ifferent G protein signaling pathways has different effects on MAPKs a nd differentiation in PC12 cells, with G(q) signaling pathways activat ing all three major MAPK pathways.