B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells

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CRH is a key regulator of neuroendocrine, autonomic, and behavioral response to stress. CRHstimulated CRH receptor 1 (CRHR1) activates ERK1/2 depending on intracellular context. In a previous work, we demonstrated that CRH activates ERK1/2 in limbic areas of the mouse brain (hippocampus and basolate...

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Detalles Bibliográficos
Autores principales: Bonfiglio, J.J., Inda, C., Senin, S., Maccarrone, G., Refojo, D., Giacomini, D., Turck, C.W., Holsboer, F., Arzt, E., Silberstein, S.
Formato: Artículo publishedVersion
Lenguaje:Inglés
Publicado: 2013
Materias:
B Raf kinase
beta arrestin 2
calcium
calcium calmodulin dependent protein kinase II
corticotropin releasing factor
corticotropin releasing factor receptor 1
cyclic AMP
cyclic AMP dependent protein kinase
dynamin
mitogen activated protein kinase 1
protein 14 3 3
Rap1 protein
vimentin
animal cell
article
basolateral amygdala
behavior
calcium cell level
calcium transport
cellular distribution
controlled study
enzyme activation
enzyme inactivation
hippocampus
internalization
learning
mass spectrometry
memory
mouse
nerve cell plasticity
nonhuman
physiological process
priority journal
screening
Adenylate Cyclase
Animals
Arrestins
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Corticotropin-Releasing Hormone
Cyclic AMP
Endocytosis
Enzyme Activation
Hippocampus
Humans
Mice
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Models, Biological
Proto-Oncogene Proteins B-raf
Rats
Receptors, Corticotropin-Releasing Hormone
Signal Transduction
Subcellular Fractions
Time Factors
Vimentin
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_08888809_v27_n3_p491_Bonfiglio
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario:CRH is a key regulator of neuroendocrine, autonomic, and behavioral response to stress. CRHstimulated CRH receptor 1 (CRHR1) activates ERK1/2 depending on intracellular context. In a previous work, we demonstrated that CRH activates ERK1/2 in limbic areas of the mouse brain (hippocampus and basolateral amygdala). ERK1/2 is an essential mediator of hippocampal physiological processes including emotional behavior, synaptic plasticity, learning, and memory. To elucidate the molecular mechanisms by which CRH activates ERK1/2 in hippocampal neurons, we used the mouse hippocampal cell line HT22. We document for the first time that ERK1/2 activation in response to CRH is biphasic, involving a first cAMP- and B-Raf-dependent early phase and a second phase that critically depends on CRHR1 internalization and β-arrestin2. By means of mass-spectrometry-based screening, we identified B-Raf-associated proteins that coimmunoprecipitate with endogenous B-Raf after CRHR1 activation. Using molecular and pharmacological tools, the functional impact of selected B-Raf partners in CRH-dependent ERK1/2 activation was dissected. These results indicate that 14-3-3 proteins, protein kinase A, and Rap1, are essential for early CRH-induced ERK1/2 activation, whereas dynamin and vimentin are required for the CRHR1 internalization-dependent phase. Both phases of ERK1/2 activation depend on calcium influx and are affected by calcium/calmodulin-dependent protein kinase II inactivation. Thus, this report describes the dynamics and biphasic nature of ERK1/2 activation downstream neuronal CRHR1 and identifies several new critical components of the CRHR1 signaling machinery that selectively controls the early and late phases of ERK1/2 activation, thus providing new potential therapeutic targets for stress-related disorders. © 2013 by The Endocrine Society.

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