Extracellular Signal-Regulated Kinase 1/2 Activation by Myometrial Oxytocin Receptor Involves GαqGβγ and Epidermal Growth Factor Receptor Tyrosine Kinase Activation

Jun 18, 2003Endocrinology

Activation of ERK1/2 by oxytocin receptors in uterine muscle involves G-proteins and growth factor receptor signaling

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Abstract

Oxytocin increases ERK1/2 phosphorylation in myometrial cells through a Gbeta-gamma-mediated pathway.

Oxytocin receptor signals primarily through Galpha(q), yet ERK1/2 phosphorylation was not fully inhibited by blocking downstream effectors.
Inhibition of protein kinase A increased cellular cAMP and affected oxytocin-induced ERK1/2 phosphorylation.
EGFR activation plays a significant role in oxytocin-induced ERK1/2 phosphorylation, as shown by the efficacy of the EGFR tyrosine kinase inhibitor AG1478.
Inhibition of intracellular calcium influx blocked ERK1/2 phosphorylation, indicating its importance in the pathway.

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The mechanisms by which oxytocin (OT) stimulates extracellular signal-regulated kinase 1/2 (ERK1/2) are only partially understood. OT receptor (OTR) signals predominantly through Galpha(q), but ERK1/2 phosphorylation (ERK1/2-P) in PHM1 myometrial cells was not eliminated by inhibition of downstream effectors such as phospholipase C or protein kinase C. Inconsistent with a Galpha(i)-coupled response, pertussis toxin inhibition of OT-induced ERK1/2-P was reversed by the protein kinase A inhibitors Rp-cAMPS and KT5720. Consistent with an inhibitory role for protein kinase A, pertussis toxin pretreatment raised cellular cAMP and 8-(4-chlorophenylthio)-cAMP inhibited OT-induced ERK1/2-P. Attenuation of the OT response by the Gbetagamma scavenger carboxyl terminus of the beta-adrenergic receptor kinase implicated a Gbetagamma-mediated pathway. In both COSM6 cells overexpressing OTR (OTR-COSM6) and in PHM1 cells, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 markedly reduced OT-induced ERK1/2-P, whereas the platelet-derived growth factor receptor tyrosine kinase inhibitor AG1296 had no effect. Furthermore, OT increased EGFR tyrosine phosphorylation in OTR-COSM6 cells, which was inhibited by AG1478 or EGTA plus thapsigargin pretreatment. AG1478 did not affect inositol 1,4,5-triphosphate production by OT or protein kinase C-stimulated ERK1/2-P but completely blocked ionomycin-induced ERK1/2-P and EGFR tyrosine phosphorylation. In both OTR-COSM6 and PHM1 cells, EGTA reduced OT-stimulated ERK1/2-P; no ERK1/2-P was observed when intracellular calcium increases were blocked by pretreatment with thapsigargin plus EGTA. These data are consistent with activation of a Gbetagamma-mediated pathway as a consequence of Galpha(q) activation in myometrium and OTR-COSM6 cells that results in increased ERK1/2-P. This pathway involves both EGFR activation and an influence of calcium.

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Extracellular Signal-Regulated Kinase 1/2 Activation by Myometrial Oxytocin Receptor Involves GαqGβγ and Epidermal Growth Factor Receptor Tyrosine Kinase Activation

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