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Molecular determinants and feedback circuits regulating type 2 CRH receptor signal integration
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Markovic, Danijel, Punn, Anu, Lehnert, Hendrik and Grammatopoulos, Dimitris (2011) Molecular determinants and feedback circuits regulating type 2 CRH receptor signal integration. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1813 (Number 5). pp. 896-907. doi:10.1016/j.bbamcr.2011.02.005 ISSN 0167-4889.
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Official URL: http://dx.doi.org/10.1016/j.bbamcr.2011.02.005
Abstract
In most target tissues, the adenylyl cyclase/cAMP/PKA, the extracellular signal regulated kinase and the protein kinase B/Akt are the main pathways employed by the type 2 corticotropin-releasing hormone receptor to mediate the biological actions of urocortins (Ucns) and CRH. To decipher the molecular determinants of CRH-R2 signaling, we studied the signaling pathways in HEK293 cells overexpressing recombinant human CRH-R2 beta receptors. Use of specific kinase inhibitors showed that the CRH-R2 beta cognate agonist. Ucn 2, activated extracellular signal regulated kinase in a phosphoinositide 3-kinase and cyclic adenosine monophosphate/PKA-dependent manner with contribution from Epac activation. Ucn 2 also induced PICA-dependent association between AKAP250 and CRH-R2 beta that appeared to be necessary for extracellular signal regulated kinase activation. PKB/Akt activation was also mediated via pertussis toxin-sensitive G-proteins and PI3-K activation but did not require cAMP/PKA, Epac or protein kinase C for optimal activation. Potential feedback mechanisms that target the CRH-R2 beta itself and modulate receptor trafficking and endocytosis were also investigated. Indeed, our results suggested that inhibition of either PKA or extracellular signal regulated kinase pathway accelerates CRH-R2 beta endocytosis. Furthermore, Ucn 2-activated extracellular signal regulated kinase appeared to target beta-arrestin1 and modulate, through phosphorylation at Ser412, beta-arrestin1 translocation to the plasma membrane and CRH-R2 beta internalization kinetics. Loss of this "negative feedback" mechanism through inhibition of the extracellular signal regulated kinase activity resulted in significant attenuation of Ucn 2-induced cAMP response, whereas Akt phosphorylation was not affected by altered receptor endocytosis. These findings reveal a complex interplay between the signaling molecules that allow "fine-tuning" of CRH-R2 beta functional responses and regulate signal integration. (C) 2011 Elsevier B.V. All rights reserved.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QP Physiology | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||
Library of Congress Subject Headings (LCSH): | Corticotropin releasing hormone -- Receptors, Cellular signal transduction, Protein kinases | ||||
Journal or Publication Title: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | ||||
Publisher: | Elsevier | ||||
ISSN: | 0167-4889 | ||||
Official Date: | 2011 | ||||
Dates: |
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Volume: | Volume 1813 | ||||
Number: | Number 5 | ||||
Page Range: | pp. 896-907 | ||||
DOI: | 10.1016/j.bbamcr.2011.02.005 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Funder: | Wellcome Trust (London, England) |
Data sourced from Thomson Reuters' Web of Knowledge
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