Structural domains determining signalling characteristics of the CRH-receptor type 1 variant R1 beta and response to PKC phosphorylation
Teli, Thalia, Markovic, Danijela, Hewitt, Margaret E., Levine, Michael A., Hillhouse, Edward W. and Grammatopoulos, Dimitris K.. (2008) Structural domains determining signalling characteristics of the CRH-receptor type 1 variant R1 beta and response to PKC phosphorylation. Cellular Signalling, Vol.20 (No.1). pp. 40-49. ISSN 0898-6568Full text not available from this repository.
Official URL: http://dx.doi.org/10.1016/j.cellsig.2007.08.014
Mammalian adaptive mechanisms to stressful stimuli involve release of corticotropin-releasing hormone (CRH) and downstream activation of specific G-protein-coupled 7 transmembrane domain receptors. These CRH receptors (CRH-R) are expressed as multiple mRNA spliced variants. In contrast to other mammals, the human type 1 CRH-R gene contains an additional exon (exon 6) that needs to be spliced out in order to generate the fully active CRH-R1 alpha. Transcription of all 14 exons results in a CRH-R1 variant (CRH-R1 beta) with an extended 1st intracellular loop (IC1); this sequence modification impairs signalling activity and alters receptor responsiveness to PKC-induced phosphorylation that leads to signalling desensitization and receptor endocytosis. To elucidate structure-function relationships and delineate sequences involved in CRH-R1 beta properties, site directed mutagenesis was used to introduce a number of specific mutations into IC1 of CRH-R1 beta as well as replace specific phospho-acceptor residues within the aminoacid sequence of CRH-R1 alpha and CRH-R1 beta Mutant receptors were transiently expressed in human embryonic kidney (HEK293) cells and tested for their abilities to increase intracellular cAMP and their response to PKC-induced phosphorylation. Results identified a penta-aminoacid cassette within the 29-aminoacid insert of CRH-R1 beta, which contains multiple positive charged aminoacids (F-170-R-174), as an important structural determinant for the impaired cAMP response. Furthermore, serine at position 408 in the carboxy-termimis appears to be important for mediating CRI-R1 alpha resistance, but not CRH-R1 beta susceptibility, to PKC-induced desensitization and internalization. These findings provide new insights about the structural determinants of CRH-R1 coupling to Gs proteins and response to protein kinase phosphorylation. (C) 2007 Elsevier Inc. All rights reserved.
|Item Type:||Journal Article|
|Subjects:||Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
|Divisions:||Faculty of Medicine > Warwick Medical School > Translational & Systems Medicine > Metabolic and Vascular Health
Faculty of Medicine > Warwick Medical School
|Library of Congress Subject Headings (LCSH):||Corticotropin releasing hormone -- Receptors, Protein kinase C, Arrestins, Phosphorylation|
|Journal or Publication Title:||Cellular Signalling|
|Official Date:||January 2008|
|Number of Pages:||10|
|Page Range:||pp. 40-49|
|Access rights to Published version:||Restricted or Subscription Access|
|Funder:||Wellcome Trust (London, England), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), City of Coventry General Charities|
 E.W. Hillhouse, D.K. Grammatopoulos, Endocr. Rev. 27 (2006) 260.
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