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Title: | Identification of a novel corticotropin-releasing hormone type 1β-like receptor variant lacking exon 13 in human pregnant myometrium regulated by estradiol-17β and progesterone |
Authors: | Markovic, D Chen, J Hillhouse, EW Grammatopoulos, DK |
Keywords: | Corticotropin-releasing hormone (CRH);CRH receptors;CRH peptides;Human pregnant myometrium |
Issue Date: | 2010 |
Publisher: | Endocrine Society |
Citation: | Endocrinology, 151(10), 4959 - 4968, 2010 |
Abstract: | Two types of CRH receptors mediate the diverse biological functions of CRH and CRH-related peptides. The type 1 CRH-R (CRH-R1) is extensively targeted by pre-mRNA splicing mechanisms that give rise to multiple mRNA splice variants. RT-PCR amplification of CRH-R1 sequences from human myometrium yielded cDNAs that encode a novel CRH-R1 splice variant with structural characteristics identical with CRH-R1β except a 14-amino acid deletion in the seventh transmembrane domain characteristic of the CRH-R1d. Transient expression of the hybrid CRH-R1 variant (CRH-R1β/d) in human embryonic kidney 293 cells revealed primarily intracellular expression, although some plasma membrane protein expression was also detectable. CRH bound to CRH-R1β/d with affinity comparable with the CRH-R1β; however, it was unable to stimulate adenylyl cyclase or other second messengers. Using a semiquantitative RT-PCR assay, CRH-R1β/d mRNA transcript was detected in human pregnant, but not nonpregnant, myometrium as early as 31 wk of gestation. Furthermore, in human pregnant myometrial cells, the relative expression of CRH-R1β and CRH-R1β/d mRNA appeared to be regulated by steroids; CRH-R1β/d mRNA expression was increased by estradiol-17β, whereas CRH-R1β mRNA levels were increased by progesterone. Progesterone also substantially increased CRH-R1α mRNA levels and cellular responsiveness to CRH as determined by increased agonist binding and cAMP production as well as resistance to CRH-R heterologous desensitization by phorbol esters. These results provide novel evidence for distinct patterns of CRH-R1 splicing and identify specific steroid-mediated regulation of CRH-R1 variant expression, which might be important for modulating CRH actions during human pregnancy and labour. |
Description: | Copyright © 2010 by The Endocrine Society. |
URI: | http://press.endocrine.org/doi/full/10.1210/en.2010-0622 http://bura.brunel.ac.uk/handle/2438/8454 |
DOI: | http://dx.doi.org/10.1210/en.2010-0622 |
ISSN: | 0013-7227 |
Appears in Collections: | Biological Sciences Publications Dept of Life Sciences Research Papers |
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