Miller, L J

Class B guanine nucleotide‐binding protein GPCRs share heptahelical topology and signalling via coupling with heterotrimeric G proteins typical of the entire superfamily of GPCRs. However, they also exhibit substantial structural differences from the more extensively studied class A GPCRs. Even their helical bundle region, most conserved across the superfamily, is predicted to differ from that of class A GPCRs. Much is now known about the conserved structure of the amino‐terminal domain of class B GPCRs, coming from isolated NMR and crystal structures, but the orientation of that domain relative to the helical bundle is unknown, and even less is understood about the conformations of the juxtamembranous amino‐terminal tail or of the extracellular loops linking the transmembrane segments. We now review what is known about the structure and function of these regions of class B GPCRs. This comes from indirect analysis of structure–function relationships elucidated by mutagenesis and/or ligand modification and from the more direct analysis of spatial approximation coming from photoaffinity labelling and cysteine trapping studies. Also reviewed are the limited studies of structure of some of these regions. No dominant theme was recognized for the structures or functional roles of distinct regions of these juxtamembranous portions of the class B GPCRs. Therefore, it is likely that a variety of molecular strategies can be engaged for docking of agonist ligands and for initiation of conformational changes in these receptors that would be expected to converge to a common molecular mechanism for activation of intracellular signalling cascades.Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐5

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.