title: Receptor activity-modifying protein-dependent impairment of calcitonin receptor splice variant Δ(1-47)hCT((a))  function.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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
  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.
authors.affiliation: School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: T
authors.initials: T
authors.lastname: Qi
authors.forename: M
authors.initials: M
authors.lastname: Dong
authors.forename: H A
authors.initials: HA
authors.lastname: Watkins
authors.forename: D
authors.initials: D
authors.lastname: Wootten
authors.forename: L J
authors.initials: LJ
authors.lastname: Miller
authors.forename: D L
authors.initials: DL
authors.lastname: Hay
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D020033:Protein Isoforms; D058261:Receptor Activity-Modifying Proteins / Q000235:genetics / Q000378:metabolism*; D018003:Receptors, Calcitonin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D050799:STAT5 Transcription Factor
chemical_list: D010455:Peptides; D020033:Protein Isoforms; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D050799:STAT5 Transcription Factor; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3