Glucagon Receptor Activates Extracellular Signal-Regulated Protein Kinase 1/2 via cAMP-Dependent Protein Kinase

We prepared a stable cell line expressing the glucagon receptor to characterize the effect of Gs-coupled receptor stimulation on extracellular signal-regulated protein kinase 1/2 (ERK1/2) activity. Glucagon treatment of the cell line caused a dose-dependent increase in cAMP concentration, activation...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-08, Vol.98 (18), p.10102-10107
Main Authors: Jiang, Youwei, Cypess, Aaron M., Muse, Evan D., Wu, Cui-Rong, Unson, Cecilia G., Merrifield, R. B., Sakmar, Thomas P.
Format: Article
Language:English
Subjects:
Agonists
Animals
Antibodies
Biochemistry
Biological Sciences
Calcium
Calcium - metabolism
Cell Line
Cell lines
Cells
Cyclic AMP-Dependent Protein Kinases - metabolism
Enzyme Activation - drug effects
Glucagon - pharmacology
Glucagon receptors
GTP-Binding Proteins - metabolism
HEK293 cells
Humans
Inositol phosphates
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - metabolism
Phosphorylation
Pretreatment
Proteins
Rats
Receptors
Receptors, Glucagon - genetics
Receptors, Glucagon - metabolism
Signal Transduction
Transfection
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Summary:We prepared a stable cell line expressing the glucagon receptor to characterize the effect of Gs-coupled receptor stimulation on extracellular signal-regulated protein kinase 1/2 (ERK1/2) activity. Glucagon treatment of the cell line caused a dose-dependent increase in cAMP concentration, activation of cAMP-dependent protein kinase (PKA), and transient release of intracellular calcium. Glucagon treatment also caused rapid dose-dependent phosphorylation and activation of mitogen-activated protein kinase kinase/ERK kinase (MEK1/2) and ERK1/2. Inhibition of either PKA or MEK1/2 blocked ERK1/2 activation by glucagon. However, no significant activation of several upstream activators of MEK, including Ras, Rap1, and Raf, was observed in response to glucagon treatment. In addition, chelation of intracellular calcium reduced glucagon-mediated ERK1/2 activation. In transient transfection experiments, glucagon receptor mutants that bound glucagon but failed to increase intracellular cAMP and calcium concentrations showed no glucagon-stimulated ERK1/2 phosphorylation. We conclude that glucagon-induced MEK1/2 and ERK1/2 activation is mediated by PKA and that an increase in intracellular calcium concentration is required for maximal ERK activation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.131200398