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Regulation of Corticotropin-Releasing Hormone Type 2 Receptors by Multiple Promoters and Alternative Splicing: Identification of Multiple Splice Variants

Department of Pathology (R.D.C.), University of Cambridge, Cambridge CB2 1QP, United Kingdom; Department of Biological Sciences (T.K., J.C., A.E.), University of Warwick, Coventry CV4 7AL, United Kingdom; and The Medical School (E.W.H.), University of Leeds, Leeds LS2 9NL, United Kingdom

Address all correspondence and requests for reprints to: Edward W. Hillhouse, Office of the Dean, Worsley Building, The Medical School, The University of Leeds, Leeds, LS2 9NL, United Kingdom. E-mail: e.w.hillhouse{at}leeds.ac.uk.

We demonstrate that multiple promoters and alternate splicing regulate expression of the human CRH receptor type 2 (CRHR2) gene. We show that flanking regions to the first exons drive promoter activity in both endogenously and nonendogenously expressing cell lines. Putative promoter elements have been identified that are conserved between species, including the comparison of CRHR2 in nonhuman primates that was previously known only in humans, which may be responsible for subtype tissue specific regulation. We have identified novel transcripts produced by alternate splicing of the first exon of CRHR2_ß (ß1a) with various combinations of the 5' exons including a novel exon (ß1c) spliced to the common exons. The 5' structure of the gene permits many other combinations of alternate splicing that may arise as part of a regulatory mechanism controlling functional receptor expression. The 5'-untranslated region of the first exons has been extended; and 3' acceptor sites identified within the 5' untranslated region of CRHR2 and CRHR2 are used during alternate splicing of CRHR2_ß upstream exons. This has important implications because various reports on the expression of CRHR2 and CRHR2 have been unable to discriminate between the functional receptor and CRHR2_ß alternate splice variants. Only the described sequences upstream of the 3' splice site are unique to CRHR2 and CRHR2.

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