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 0898-6568

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Abstract

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 > Clinical Sciences Research Institute (CSRI) Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health
Library of Congress Subject Headings (LCSH):	Corticotropin releasing hormone -- Receptors, Protein kinase C, Arrestins, Phosphorylation
Journal or Publication Title:	Cellular Signalling
Publisher:	Elsevier
ISSN:	0898-6568
Date:	January 2008
Volume:	Vol.20
Number:	No.1
Number of Pages:	10
Page Range:	pp. 40-49
Identification Number:	10.1016/j.cellsig.2007.08.014
Status:	Peer Reviewed
Publication Status:	Published
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
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URI:	http://wrap.warwick.ac.uk/id/eprint/30689

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