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Intracellular mechanisms regulating corticotropin-releasing hormone receptor-2 beta endocytosis and interaction with extracellularly regulated kinase 1/2 and p38 mitogen-activated protein kinase signaling cascades
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Markovic, Danijela, Punn, Anu, Lehnert, Hendrik and Grammatopoulos, Dimitris (2008) Intracellular mechanisms regulating corticotropin-releasing hormone receptor-2 beta endocytosis and interaction with extracellularly regulated kinase 1/2 and p38 mitogen-activated protein kinase signaling cascades. Molecular Endocrinology, Vol.22 (No.3). pp. 689-706. doi:10.1210/me.2007-0136
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Official URL: http://dx.doi.org/10.1210/me.2007-0136
Abstract
Many important physiological roles of the urocortin (UCN) family of peptides as well as CRH involve the type 2 CRH receptor (CRH-R2) and downstream activation of multiple pathways. To characterize molecular determinants of CRH-R2 functional activity, we used HEK293 cells overexpressing recombinant CRH-R2 beta and investigated mechanisms involved in attenuation of CRH-R2 signaling activity and uncoupling from intracellular effectors. CRH-R2 beta-mediated adenylyl cyclase activation was sensitive to homologous desensitization induced by pretreatment with either UCN-II or the weaker agonist CRH. CRH-R2 beta activation induced transient beta-arrestin1 and beta-arrestin2, as well as clathrin, recruitment to the plasma membrane. beta-Arrestin2 appeared to be the main beta-arrestin subtype associated with the receptor. This was followed by CRH-R2 beta endocytosis in a mechanism that exhibited distinct agonist-dependent temporal characteristics. CRH-R2 beta also induced transient activation of the ERK1/2 and p38MAPK signaling cascades that peaked at 5 min and returned to basal within 20-30 min. Unlike p38MAPK, activated ERK1/2 was localized both in the cytoplasm and nucleus. Experiments employing inhibitors of receptor endocytosis showed that CRH-R2 beta-MAPK interaction does not require beta-arrestin, clathrin, or receptor endocytosis. Site-directed mutagenesis studies on CRH-R2 beta C terminus showed that the amino acid cassette TAAV at the end of the C terminus is important for CRH-R2 beta signaling because loss of a potential phospho-acceptor site in mutant receptors containing deletion or Ala substitution of the cassette TAAV resulted in reduced ERK1/2 activation and accelerated receptor internalization. These findings provide new insights about the signaling mechanisms regulating CRH-R2 beta functional activity and determining its biological responses.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | R Medicine > RC Internal medicine | ||||
| Divisions: | Faculty of Science > Mathematics | ||||
| Journal or Publication Title: | Molecular Endocrinology | ||||
| Publisher: | Endocrine Society | ||||
| ISSN: | 0888-8809 | ||||
| Official Date: | March 2008 | ||||
| Dates: |
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| Volume: | Vol.22 | ||||
| Number: | No.3 | ||||
| Number of Pages: | 18 | ||||
| Page Range: | pp. 689-706 | ||||
| DOI: | 10.1210/me.2007-0136 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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