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Structural determinants critical for localization and signaling within the seventh transmembrane domain of the type 1 corticotropin releasing hormone receptor : lessons from the receptor variant R1d
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Markovic, Danijela, Lehnert, Hendrik, Levine, Michael A. and Grammatopoulos, Dimitris (2008) Structural determinants critical for localization and signaling within the seventh transmembrane domain of the type 1 corticotropin releasing hormone receptor : lessons from the receptor variant R1d. Molecular Endocrinology, Volume 22 (Number 11). pp. 2505-2519. doi:10.1210/me.2008-0177 ISSN 0888-8809.
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Official URL: http://dx.doi.org/10.1210/me.2008-0177
Abstract
The type 1 CRH receptor (CRH-R1) plays a fundamental role in homeostatic adaptation to stressful stimuli. CRH-R1 gene activity is regulated through alternative splicing and generation of various CRH-R1 mRNA variants. One such variant is the CRH-R1d, which has 14 amino acids missing from the putative seventh transmembrane domain due to exon 13 deletion, a splicing event common to other members of the B1 family of G protein-coupled receptors. In this study, using overexpression of recombinant receptors in human embryonic kidney 293 and myometrial cells, we showed by confocal microscopy that in contrast to CRH-R1 alpha, the R1d variant is primarily retained in the cytoplasm, although some cell membrane expression is also evident. Use of antibodies against the CRH-R1 C terminus in nonpermeabilized cells showed that membrane-expressed CRH-R1d contains an extracellular C terminus. Interestingly, treatment of CRH-R1d-expressing cells with CRH (100 nM) for 45-60 min elicited functional responses associated with a significant reduction of plasma membrane receptor expression, redistribution of intracellular receptors, and increased receptor degradation. Site-directed mutagenesis studies identified the cassette G(356)- F-358 within transmembrane domain 7 as crucial for CRH-R1 alpha stability to the plasma membrane because deletion of this cassette caused substantial intracellular localization of CRH-R1 alpha. Most importantly, coexpression studies between CRH-R1d and CRH-R2 beta demonstrated that the CRH-R2 beta could partially rescue CRH-R1d membrane expression, and this was associated with a significant attenuation of urocotrin II-induced cAMP production and ERK1/2 and p38MAPK activation, suggesting that CRH-R1d might specifically induce heterologous impairment of CRH-R2 signaling responses. This mechanism appears to involve accelerated CRH-R2 beta endocytosis. (Molecular Endocrinology 22: 2505-2519, 2008)
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Hormone receptors, Ligand binding (Biochemistry), Phosphorylation, Endocytosis, Cellular signal transduction | ||||
| Journal or Publication Title: | Molecular Endocrinology | ||||
| Publisher: | Endocrine Society | ||||
| ISSN: | 0888-8809 | ||||
| Official Date: | November 2008 | ||||
| Dates: |
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| Volume: | Volume 22 | ||||
| Number: | Number 11 | ||||
| Number of Pages: | 15 | ||||
| Page Range: | pp. 2505-2519 | ||||
| DOI: | 10.1210/me.2008-0177 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | Wellcome Trust (London, England) |
Data sourced from Thomson Reuters' Web of Knowledge
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