Integration of G protein signals by extracellular signal‐regulated protein kinases in SK‐N‐MC neuroepithelioma cells

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Abstract
Mammalian cells often receive multiple extracellular stimuli under physiological conditions, and the various signaling inputs have to be integrated for the processing of complex biological responses. G protein‐coupled receptors (GPCRs) are critical players in converting extracellular stimuli into intracellular signals. In this report, we examined the integration of different GPCR signals by mitogen‐activated protein kinases (MAPKs) using the SK‐N‐MC human brain neuroepithelioma cells as a neuronal model. Stimulation of the Gi‐coupled neuropeptide Y1and Gq‐coupled muscarinic M1acetylcholine receptors, but not the Gs‐coupled dopamine D1receptor, led to the activation of extracellular signal‐regulated kinase (ERK). All three receptors were also capable of stimulating c‐Jun NH2‐terminal kinases (JNK) and p38 MAPK. The Gi‐mediated ERK activation was completely suppressed upon inhibition of Src tyrosine kinases by PP1, while the Gq‐induced response was suppressed by both PP1 and the Ca2+chelator, BAPTA‐AM. In contrast, activations of JNK and p38 by Gs‐, Gi‐, and Gq‐coupled receptors were sensitive to PP1 and BAPTA‐AM pretreatments. Simultaneous stimulation of Gi‐ and Gq‐coupled receptors resulted in the synergistic activation of ERK, but not JNK or p38 MAPK. The Gi/Gq‐induced synergistic ERK activation was PTX‐sensitive, and appeared to be a co‐operative effect between Ca2+and Src family tyrosine kinases. Enhanced ERK activation was associated with an increase in CREB phosphorylation, while the JNK and p38‐responsive transcription factor ATF‐2 was weakly enhanced upon Gi/Gq‐induction. This report provides evidence that G protein signals can be integrated at the level of MAPK, resulting in differential effects on ERK, JNK and p38 MAPK in SK‐N‐MC cells.

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