Markovic, Danijela, Punn, Anu, Lehnert, Hendrik and Grammatopoulos, Dimitris K.. (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. ISSN 0888-8809

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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
Date:	March 2008
Volume:	Vol.22
Number:	No.3
Number of Pages:	18
Page Range:	pp. 689-706
Identification Number:	10.1210/me.2007-0136
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/30494

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