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Extracellular signal-regulated kinase 1/2 activation by myometrial oxytocin receptor involves Galpha(q)Gbetagamma and epidermal growth factor receptor tyrosine kinase activation. 2003

Miao Zhong, and Ming Yang, and Barbara M Sanborn
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.

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.

UI MeSH Term Description Entries
D009215 Myometrium The smooth muscle coat of the uterus, which forms the main mass of the organ. Uterine Muscle,Muscle, Uterine,Muscles, Uterine,Uterine Muscles
D010738 Type C Phospholipases A subclass of phospholipases that hydrolyze the phosphoester bond found in the third position of GLYCEROPHOSPHOLIPIDS. Although the singular term phospholipase C specifically refers to an enzyme that catalyzes the hydrolysis of PHOSPHATIDYLCHOLINE (EC 3.1.4.3), it is commonly used in the literature to refer to broad variety of enzymes that specifically catalyze the hydrolysis of PHOSPHATIDYLINOSITOLS. Lecithinase C,Phospholipase C,Phospholipases, Type C,Phospholipases C
D011493 Protein Kinase C An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. Calcium Phospholipid-Dependent Protein Kinase,Calcium-Activated Phospholipid-Dependent Kinase,PKC Serine-Threonine Kinase,Phospholipid-Sensitive Calcium-Dependent Protein Kinase,Protein Kinase M,Calcium Activated Phospholipid Dependent Kinase,Calcium Phospholipid Dependent Protein Kinase,PKC Serine Threonine Kinase,Phospholipid Sensitive Calcium Dependent Protein Kinase,Phospholipid-Dependent Kinase, Calcium-Activated,Serine-Threonine Kinase, PKC
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014162 Transfection The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES. Transfections
D043802 GTP-Binding Protein alpha Subunits, Gq-G11 A family of heterotrimeric GTP-binding protein alpha subunits that activate TYPE C PHOSPHOLIPASES dependent signaling pathways. The Gq-G11 part of the name is also spelled Gq/G11. G alpha q Protein,G-Protein, Gq,G-Protein, Gq alpha Family,G-Protein, Gq-G11 alpha Family,G alpha Protein q,G alpha11 Protein,G-Protein, G11,G-Protein, Gq-G11,GTP-Binding Protein alpha Subunit, G11,GTP-Binding Protein alpha Subunit, Gq,Galpha11 Protein,Galphaq Protein,Gq Protein,Gq-G11 G-Protein Family,Gq-G11 G-Proteins,Family, Gq-G11 G-Protein,G Protein, G11,G Protein, Gq,G Protein, Gq G11,G Protein, Gq G11 alpha Family,G Protein, Gq alpha Family,G-Protein Family, Gq-G11,G-Proteins, Gq-G11,G11 G-Protein,GTP Binding Protein alpha Subunit, G11,GTP Binding Protein alpha Subunit, Gq,GTP Binding Protein alpha Subunits, Gq G11,Gq G-Protein,Gq G11 G Protein Family,Gq G11 G Proteins,Gq-G11 G-Protein,Protein, G alpha11,Protein, Galpha11,alpha11 Protein, G
D044387 GTP-Binding Protein beta Subunits Heterotrimeric GTP-binding protein subunits that tightly associate with GTP-BINDING PROTEIN GAMMA SUBUNITS. A dimer of beta and gamma subunits is formed when the GTP-BINDING PROTEIN ALPHA SUBUNIT dissociates from the GTP-binding protein heterotrimeric complex. The beta-gamma dimer can play an important role in signal transduction by interacting with a variety of second messengers. G-Protein beta Subunit,GTP-Binding Protein beta Subunit,G Protein beta Subunit,GTP Binding Protein beta Subunit,GTP Binding Protein beta Subunits,Subunit, G-Protein beta,beta Subunit, G-Protein

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