Watkins, Harriet A.

Background and PurposeAlternative splicing expands proteome diversity toGPCRs. Distinct receptor variants have been identified for a secretin familyGPCR, 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 humanCTRlacks the first 47 residues at itsNterminus [Δ(1–47)hCT(a)]. However, very little is known about the pharmacology of this variant or its ability to interact withRAMPsto form amylin receptors.Experimental ApproachΔ(1–47)hCT(a)was characterized both with and withoutRAMPsinCos7and/orHEK293Scells. The receptor expression (ELISAassays) and function (cAMPandpERK1/2 assays) for up to six agonists and two antagonists were determined.Key ResultsDespite lacking 47 residues at theNterminus, 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 withRAMP1and formed a functional amylin receptor; this also appeared to be the case withRAMP3. On the other hand, its interaction withRAMP2and resultant amylin receptor was reduced to a greater extent.Conclusions and ImplicationsΔ(1–47)hCT(a)acts as a functional receptor at the cell surface. It exhibits altered receptor function, depending on whether it associates with aRAMPand whichRAMPit interacts with. Therefore, the presence of this variant in tissues will potentially contribute to altered peptide binding and signalling, depending on theRAMPdistribution in tissues.