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J. Biol. Chem., Vol. 278, Issue 25, 23085-23093, June 20, 2003

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The Alternatively Spliced e13 Transcript of the Rabbit Calcitonin Receptor Dimerizes with the C1a Isoform and Inhibits Its Surface Expression^*

Thomas Seck , Roland Baron and William C. Horne

From the Departments of Cell Biology and Orthopedics, Yale University School of Medicine, New Haven, Connecticut 06510

Numerous alternatively spliced transcripts are generated from the gene for the G protein-coupled calcitonin receptor, and some of the splice variants show differences in receptor-mediated signaling events. This study showed that the e13 splice variant of the rabbit calcitonin receptor is expressed together with the more common C1a in osteoclast-like cells. Since other G protein-coupled receptors form homo- or heterodimers, we examined whether heterodimerization of the calcitonin receptor splice variants occurs and, if so, whether it affects the function of the receptor. Homodimers of both isoforms and e13/C1a heterodimers were detected by co-immunoprecipitation and fluorescence resonance energy transfer analysis. In contrast to the C1a isoform, the e13 isoform was not efficiently transported to the cell surface. When co-expressed with the C1a splice variant, the e13 isoform colocalized with the C1a isoform within the cell but not at the cell surface. Furthermore, the overexpression of the e13 variant led to a significant reduction of the C1a surface expression and consequently a reduction of the cAMP response and Erk phosphorylation after ligand stimulation. We therefore suggest that the e13 variant of the rabbit calcitonin receptor acts to regulate the surface expression of the C1a isoform.

Received for publication, November 4, 2002 , and in revised form, March 18, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SE 999/1-1 (to T. S.) and National Institutes of Health Grant DE-04724 (to R. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Internal Medicine, Berufsgenossenschaftliche Kliniken Bergmannsheil, University of Bochum, D-44789 Bochum, Germany. Tel.: 49-234-3020; E-mail: thomas_seck{at}hotmail.com.

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