B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells
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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2013
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08888809_v27_n3_p491_Bonfiglio http://hdl.handle.net/20.500.12110/paper_08888809_v27_n3_p491_Bonfiglio |
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paper:paper_08888809_v27_n3_p491_Bonfiglio2023-06-08T15:47:03Z B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells Bonfiglio, Juan José Refojo, Damián Giacomini, Damiana Paula Silberstein Cuña, Susana Iris 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 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. Fil:Bonfiglio, J.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Refojo, D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Giacomini, D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Silberstein, S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08888809_v27_n3_p491_Bonfiglio http://hdl.handle.net/20.500.12110/paper_08888809_v27_n3_p491_Bonfiglio |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Bonfiglio, Juan José Refojo, Damián Giacomini, Damiana Paula Silberstein Cuña, Susana Iris B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells |
| topic_facet |
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 |
| description |
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. |
| author |
Bonfiglio, Juan José Refojo, Damián Giacomini, Damiana Paula Silberstein Cuña, Susana Iris |
| author_facet |
Bonfiglio, Juan José Refojo, Damián Giacomini, Damiana Paula Silberstein Cuña, Susana Iris |
| author_sort |
Bonfiglio, Juan José |
| title |
B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells |
| title_short |
B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells |
| title_full |
B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells |
| title_fullStr |
B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells |
| title_full_unstemmed |
B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 cells |
| title_sort |
b-raf and crhr1 internalization mediate biphasic erk1/2 activation by crh in hippocampal ht22 cells |
| publishDate |
2013 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08888809_v27_n3_p491_Bonfiglio http://hdl.handle.net/20.500.12110/paper_08888809_v27_n3_p491_Bonfiglio |
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| _version_ |
1768542088011448320 |