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Vol. 53, Issue 4, 613-622, April 1998
Dimer-Mediated Pathway Contributes to
Mitogen-Activated Protein Kinase Activation by Thyrotropin-Releasing
Hormone Receptors in Transfected COS-7 Cells
Departamento de Bioquímica y Biología Molecular,
Facultad de Medicina, Universidad de Oviedo, E-33006, Oviedo, Spain
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 
subunits (t), an agent known to sequester free G
protein 
dimers. However, the inhibitory potency of t on
TRH-induced activation is about half of that obtained in cells
transfected with m2 muscarinic receptors, which activate MAPK
exclusively through dimers. The effect of t is also additive
with that of GF109203X but not with that of p21N17ras. MAPK
activation is not induced by the constitutively active form of
G
q 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 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.
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