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Molecular Pharmacology

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Research ArticleArticle

A G Protein βγ Dimer-Mediated Pathway Contributes to Mitogen-Activated Protein Kinase Activation by Thyrotropin-Releasing Hormone Receptors in Transfected COS-7 Cells

Teresa Palomero, Francisco Barros, Donato del Camino, Cristina G. Viloria and Pilar de la Peña
Molecular Pharmacology April 1998, 53 (4) 613-622; DOI: https://doi.org/10.1124/mol.53.4.613
Teresa Palomero
Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Universidad de Oviedo, E-33006, Oviedo, Spain
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Francisco Barros
Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Universidad de Oviedo, E-33006, Oviedo, Spain
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Donato del Camino
Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Universidad de Oviedo, E-33006, Oviedo, Spain
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Cristina G. Viloria
Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Universidad de Oviedo, E-33006, Oviedo, Spain
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Pilar de la Peña
Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Universidad de Oviedo, E-33006, Oviedo, Spain
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Abstract

Activation of mitogen-activated protein kinase (MAPK) is induced by adding thyrotropin-releasing hormone (TRH) to COS-7 cells cotransfected with TRH receptors and an epitope-tagged MAPK. Long term treatment of the cells with pertussis toxin has no effect on TRH-induced MAPK activation. Incubation of the cells with the protein kinase C (PKC) inhibitor GF109203X causes an almost complete inhibition of MAPK activation by the PKC activator phorbol-12-myristate-13-acetate. In contrast, only ∼50% of the TRH-induced MAPK activity is inhibited by GF109203X, indicating that activation of MAPK by TRH is only partially dependent on PKC. The inhibitory effect of GF109203X is additive with that of p21N17ras, a dominant negative mutant of p21ras that exerts little effect on PKC-dependent MAPK activation by phorbol-12-myristate-13-acetate. The TRH-induced activation of MAPK also is inhibited partially by overexpression of transducin α subunits (αt), an agent known to sequester free G protein βγ dimers. However, the inhibitory potency of αt on TRH-induced activation is about half of that obtained in cells transfected with m2 muscarinic receptors, which activate MAPK exclusively through βγ dimers. The effect of αt is also additive with that of GF109203X but not with that of p21N17ras. MAPK activation is not induced by the constitutively active form of Gαq due to an inhibitory effect of its expression at a step downstream of that at which PKC-dependent and -independent routes to MAPK converge. Our results demonstrate that TRH receptors activate MAPK by a pathway only partially dependent on PKC activity. Furthermore, they indicate that βγ dimers of a pertussis and cholera toxin-insensitive G protein are involved in the PKC-independent fraction of the dual signaling route to MAPK initiated in the TRH receptor.

Footnotes

    • Received August 1, 1997.
    • Accepted December 29, 1997.
  • Send reprint requests to: Dr. Pilar de la Peña, Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Universidad de Oviedo, E-33006, Oviedo, Spain. E-mail: paco{at}bioaxp.quimica.uniovi.es

  • This work was supported by Grant PB93–1076 from Comisión Interministerial de Ciencia y Tecnologia of Spain. T. P. and D. del C. are recipients of fellowships from II Plan Regional de Investigación of Asturias (Spain). C.G.V. is a predoctoral fellow from Comisión Interministerial de Ciencia y Tecnologia of Spain. Several preliminary experiments were performed during a short term fellowship to P.P. from NATO Scientific Program in the laboratory of Dr. J. S. Gutkind (National Institute of Dental Research, National Institutes of Health).

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Molecular Pharmacology: 53 (4)
Molecular Pharmacology
Vol. 53, Issue 4
1 Apr 1998
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Research ArticleArticle

A G Protein βγ Dimer-Mediated Pathway Contributes to Mitogen-Activated Protein Kinase Activation by Thyrotropin-Releasing Hormone Receptors in Transfected COS-7 Cells

Teresa Palomero, Francisco Barros, Donato del Camino, Cristina G. Viloria and Pilar de la Peña
Molecular Pharmacology April 1, 1998, 53 (4) 613-622; DOI: https://doi.org/10.1124/mol.53.4.613

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Research ArticleArticle

A G Protein βγ Dimer-Mediated Pathway Contributes to Mitogen-Activated Protein Kinase Activation by Thyrotropin-Releasing Hormone Receptors in Transfected COS-7 Cells

Teresa Palomero, Francisco Barros, Donato del Camino, Cristina G. Viloria and Pilar de la Peña
Molecular Pharmacology April 1, 1998, 53 (4) 613-622; DOI: https://doi.org/10.1124/mol.53.4.613
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