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Molecular Endocrinology 13 (12): 2189-2202
Copyright © 1999 by The Endocrine Society

A Novel Spliced Variant of the Type 1 Corticotropin-Releasing Hormone Receptor with a Deletion in the Seventh Transmembrane Domain Present in the Human Pregnant Term Myometrium and Fetal Membranes

Dimitris K. Grammatopoulos1, Yalei Dai1, Harpal S. Randeva, Michael A. Levine, Emmanouil Karteris, Andrew J. Easton and Edward W. Hillhouse

Sir Quinton Hazell Molecular Medicine Research Centre (D.K.G., Y.D., H.S.R., E.K., A.J.E., E.W.H.) Department of Biological Sciences University of Warwick Coventry, CV4 7AL, United Kingdom The Johns Hopkins University School of Medicine (M.A.L.) Division of Pediatric Endocrinology Department of Pediatrics Baltimore, Maryland 21287

CRH exerts its actions via activation of specific G protein-coupled receptors, which exist in two types, CRH-R1 and CRH-R2, and arise from different genes with multiple spliced variants. RT-PCR amplification of CRH receptor sequences from human myometrium and fetal membranes yielded cDNAs that encode a novel CRH-R type 1 spliced variant. This variant (CRH-R1d) is present in the human pregnant myometrium at term only, which suggests a physiologically important role at the end of human pregnancy and labor. The amino acid sequence of CRH-R1d is identical to the CRH-R1{alpha} receptor except that it contains an exon deletion resulting in the absence of 14 amino acids in the predicted seventh transmembrane domain. Binding studies in HEK-293 cells stably expressing the CRH-R1d or CRH-R1{alpha} receptors revealed that the deletion does not change the binding characteristics of the variant receptor. In contrast, studies on the G protein activation demonstrated that CRH-R1d is not well coupled to the four subtypes of G proteins (Gs, Gi, Go, Gq) that CRH-R1{alpha} can activate. These data suggest that although the deleted segment is not important for CRH binding, it plays a crucial role in CRH receptor signal transduction.

Second messenger studies of the variant receptor showed that CRH and CRH-like peptides can stimulate the adenylate cyclase system, with reduced sensitivity and potency by 10-fold compared with the CRH-R1{alpha}. Furthermore, CRH failed to stimulate inositol trisphosphate production. Coexpression studies between the CRH-R1d or CRH-R1{alpha} showed that this receptor does not play a role as a dominant negative receptor for CRH.




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