UNSPECIFIED (2000) Urocortin, but not corticotropin-releasing hormone (CRH), activates the mitogen-activated protein kinase signal transduction pathway in human pregnant myometrium: An effect mediated via R1 alpha and R2 beta CRH receptor subtypes and stimulation of Gq-proteins. MOLECULAR ENDOCRINOLOGY, 14 (12). pp. 2076-2091. ISSN 0888-8809

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Abstract

CRH and CRH-related peptides such as urocortin mediate their actions in the human myometrium via activation of two distinct classes of CRH receptors, R1 and R2. These heptahelical receptors are able to stimulate a number of different intracellular signals; one key mediator of G protein-activated intracellular signaling is the cascade of p42/p44, mitogen-activated protein kinase (MAPK). We therefore hypothesized that activation of MAPK might mediate CRH and or/urocortin actions in the myometrium. In cultured human pregnant myometrial cells, urocortin but not CRH was able to induce MARK phosphorylation and activation, suggesting that in the human myometrium these two peptides have distinct actions and biological roles. To identify the particular receptor subtypes mediating this phenomenon, all known CRH receptors present in the human myometrial cells were stably expressed individually in HEK293 and CHO cells, and their ability to activate MAPK was tested. The R1 alpha and R2 beta, but not the R1 beta, R1c, or R1d, receptor subtypes were able to mediate urocortin-induced MAPK activation. The signaling components were further investigated; activation of Gs, Go, or Gi proteins did not appear to be involved, but activation of Gq with subsequent production of inositol triphosphates (IP3) and protein kinase C (PKC) activation correlated with MARK phosphorylation. Studies on Gq protein activation using [alpha-P-32]-GTP-gamma -azidoanilide and IP3 production in cells expressing the R1 alpha or R2 beta CRH receptors demonstrated that urocortin was 10 times more potent than CRH. Moreover, urocortin (UCN) generated peak responses that were 50-70% greater than CRH in activating the Gq protein and stimulating IP3 production. In conclusion, UCN acting thought multiple receptor subtypes can stimulate myometrial MAPK via induction of the Gq/phospholipase C/IP3/PKC pathway, whereas CRH-induced activation of this pathway appears to be insufficient to achieve MAPK activation.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Journal or Publication Title:	MOLECULAR ENDOCRINOLOGY
Publisher:	ENDOCRINE SOC
ISSN:	0888-8809
Date:	December 2000
Volume:	14
Number:	12
Number of Pages:	16
Page Range:	pp. 2076-2091
Publication Status:	Published
URI:	http://wrap.warwick.ac.uk/id/eprint/12746

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