Receptor activity-modifying protein-dependent impairment of calcitonin receptor splice variant Δ(1–47)hCT(a) function
Article first published online: 16 JAN 2013
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Volume 168, Issue 3, pages 644–657, February 2013
How to Cite
Qi, T., Dong, M., Watkins, H., Wootten, D., Miller, L. and Hay, D. (2013), Receptor activity-modifying protein-dependent impairment of calcitonin receptor splice variant Δ(1–47)hCT(a) function. British Journal of Pharmacology, 168: 644–657. doi: 10.1111/j.1476-5381.2012.02197.x
- Issue published online: 16 JAN 2013
- Article first published online: 16 JAN 2013
- Accepted manuscript online: 5 SEP 2012 04:33AM EST
- Manuscript Accepted: 10 AUG 2012
- Manuscript Revised: 7 AUG 2012
- Manuscript Received: 3 JUL 2012
- National Institutes of Health. Grant Number: DK46577
- G-protein coupled receptor;
- receptor activity-modifying protein;
- splice variant
Background and Purpose
Alternative splicing expands proteome diversity to GPCRs. Distinct receptor variants have been identified for a secretin family GPCR, the calcitonin receptor (CTR). The possible functional contributions of these receptor variants are further altered by their potential interactions with receptor activity-modifying proteins (RAMPs). One variant of the human CTR lacks the first 47 residues at its N terminus [Δ(1–47)hCT(a)]. However, very little is known about the pharmacology of this variant or its ability to interact with RAMPs to form amylin receptors.
Δ(1–47)hCT(a) was characterized both with and without RAMPs in Cos7 and/or HEK293S cells. The receptor expression (ELISA assays) and function (cAMP and pERK1/2 assays) for up to six agonists and two antagonists were determined.
Despite lacking 47 residues at the N terminus, Δ(1–47)hCT(a) was still able to express at the cell surface, but displayed a generalized reduction in peptide potency. Δ(1–47)hCT(a) retained its ability to interact with RAMP1 and formed a functional amylin receptor; this also appeared to be the case with RAMP3. On the other hand, its interaction with RAMP2 and resultant amylin receptor was reduced to a greater extent.
Conclusions and Implications
Δ(1–47)hCT(a) acts as a functional receptor at the cell surface. It exhibits altered receptor function, depending on whether it associates with a RAMP and which RAMP it interacts with. Therefore, the presence of this variant in tissues will potentially contribute to altered peptide binding and signalling, depending on the RAMP distribution in tissues.