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Identification of a novel corticotropin-releasing hormone type 1 beta-Like receptor variant lacking exon 13 in human pregnant myometrium regulated by estradiol-17 beta and progesterone

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Karteris, Emmanouil, Markovic, Danijela, Chen, Jing, Hillhouse, Edward W. and Grammatopoulos, Dimitris K.. (2010) Identification of a novel corticotropin-releasing hormone type 1 beta-Like receptor variant lacking exon 13 in human pregnant myometrium regulated by estradiol-17 beta and progesterone. Endocrinology, Vol.151 (No.10). pp. 4959-4968. ISSN 0013-7227

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Official URL: http://dx.doi.org/10.1210/en.2010-0622

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-R1 beta 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-R1 beta/d) in human embryonic kidney 293 cells revealed primarily intracellular expression, although some plasma membrane protein expression was also detectable. CRH bound to CRH-R1 beta/d with affinity comparable with the CRH-R1 beta; however, it was unable to stimulate adenylyl cyclase or other second messengers. Using a semiquantitative RT-PCR assay, CRH-R1 beta/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-R1 beta and CRH-R1 beta/d mRNA appeared to be regulated by steroids; CRH-R1 beta/d mRNA expression was increased by estradiol-17 beta, whereas CRH-R1 beta mRNA levels were increased by progesterone. Progesterone also substantially increased CRH-R1 alpha 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. (Endocrinology 151: 4959-4968, 2010)

Item Type:

Journal Article

Subjects:

R Medicine > RC Internal medicine

Divisions:

Faculty of Medicine > Warwick Medical School

Journal or Publication Title:

Endocrinology

Publisher:

The Endocrine Society

ISSN:

0013-7227