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(Received for publication, August 9, 1996, and in revised form, September 19, 1996)
From the Departments of Cell Biology and Orthopaedics, Yale
University School of Medicine, New Haven, Connecticut 06520-8044
The cDNA that encodes the rabbit calcitonin
receptor was cloned by screening a rabbit osteoclast library. Reverse
transcription-polymerase chain reaction amplification of calcitonin
receptor sequences from rabbit osteoclast RNA yielded cDNAs that
encode two isoforms of the calcitonin receptor. One isoform is
homologous to the C1a isoform previously identified in multiple cell
types and species, while the second, designated CTR
Volume 271, Number 49,
Issue of December 6, 1996
pp. 31127-31134
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
e13, is a
previously unidentified isoform that is apparently generated by
alternative splicing during mRNA processing that deletes exon 13, resulting in the absence of 14 amino acids in the predicted seventh
transmembrane domain. Expression of mRNA transcripts encoding the
two isoforms varies in a tissue-specific manner, with CTRe13
accounting for less than 15% of the total calcitonin receptor mRNA
in osteoclasts, kidney, and brain, but comprising at least 50% of the
transcripts in skeletal muscle and lung. The two isoforms were
expressed, and the ligand binding and signal transduction properties
were characterized. Deletion of the residues in the seventh
transmembrane domain in CTRe13 reduced the binding affinity for
salmon and human calcitonin by more than 10-fold and approximately
2-fold, respectively, resulting in a receptor that failed to
discriminate between the two forms of calcitonin. Both isoforms
activated adenylyl cyclase, with EC50 values consistent
with the difference in ligand affinities. In contrast, only the C1a
isoform, but not the CTRe13 isoform, activated phospholipase C. Thus, while the CTRe13 remains active despite the deletion of a
significant portion of its seventh transmembrane domain, it has
significantly altered ligand recognition and signal transduction
properties.
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