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This version published online on April 28, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0472
A more recent version of this article appeared on August 1, 2005
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Submitted on November 23, 2004
Accepted on April 20, 2005

The {Delta}e13 isoform of the calcitonin receptor forms a six transmembrane domain receptor with dominant negative effects on receptor surface expression and signaling

Thomas Seck, Maria Pellegrini, Ana Maria Florea, Veronique Grignoux, Roland Baron, Dale F. Mierke, and William C. Horne*

Departments of Orthopedics and Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520; Department of Endocrinology, Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany; Department of Molecular Pharmacology, Division of Biology & Medicine, Brown University, Providence, Rhode Island, 02912

* To whom correspondence should be addressed. E-mail: william.horne{at}yale.edu.

A splice variant of the rabbit calcitonin receptor (CTR{Delta}e13) which lacks the 14 amino acids of the 7th transmembrane domain that are encoded by exon 13 is poorly expressed on the cell surface, fails to mobilize intracellular calcium or activate Erk, and inhibits the cell surface expression of the full-length C1a isoform. NMR- and FACS-based experiments showed that the residual 7th transmembrane domain of CTR{Delta}e13 fails to partition into the lipid bilayer, resulting in an extracellular C-terminus. Truncating the receptor after residue 397 to delete the cytoplasmic tail resulted in reduced cell surface expression and an inability to mobilize intracellular calcium or activate Erk, but the truncated receptor did not inhibit C1a cell surface expression. In contrast, when the receptor was truncated after residue 374 to eliminate the entire 7th transmembrane domain and the C-terminal domain, the resulting receptor reduced the cell surface expression of C1a in a manner similar to that of CTR{Delta}e13. Thus, normal cell surface expression, mobilization of intracellular calcium, and Erk activation requires the cytoplasmic C-terminal tail of the calcitonin receptor, while the absence of the 7th transmembrane domain in the transmembrane helical bundle causes the dominant-negative effect on the surface expression of C1a.




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