title: Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity.
abstract: LGR7 and LGR8 are G protein-coupled receptors that belong to the leucine-rich repeat-containing G-protein coupled receptor (LGR) family, including the thyroid-stimulating hormone (TSH), LH and FSH receptors. LGR7 and LGR8 stimulate cAMP production upon binding of the cognate ligands, relaxin and insulin-like peptide 3 (INSL3), respectively. We cloned several novel splice variants of both LGR7 and LGR8 and analysed the function of four variants. LGR7.1 is a truncated receptor, including only the N-terminal region of the receptor and two leucine rich repeats. In contrast, LGR7.2, LGR7.10 and LGR 8.1 all contain an intact seven transmembrane domain and most of the extracellular region, lacking only one or two exons in the ectodomain. Our analysis demonstrates that although LGR7.10 and LGR8.1 are expressed at the cell surface, LGR7.2 is predominantly retained within cells and LGR7.1 is partially secreted. mRNA expression analysis revealed that several variants are co-expressed in various tissues. None of these variants were able to stimulate cAMP production following relaxin or INSL3 treatment. Unexpectedly, we did not detect any direct specific relaxin or INSL3 binding on any of the splice variants. The large number of receptor splice variants identified suggests an unforeseen complexity in the physiology of this novel hormone-receptor system.
authors.affiliation: Serono Research Institute, One Technology Place, Rockland, MA 02370, USA. marco.muda@serono.com
authors.forename: Marco
authors.initials: M
authors.lastname: Muda
authors.forename: Chaomei
authors.initials: C
authors.lastname: He
authors.forename: Paolo G V
authors.initials: PG
authors.lastname: Martini
authors.forename: Tania
authors.initials: T
authors.lastname: Ferraro
authors.forename: Sharon
authors.initials: S
authors.lastname: Layfield
authors.forename: Deanne
authors.initials: D
authors.lastname: Taylor
authors.forename: Colette
authors.initials: C
authors.lastname: Chevrier
authors.forename: Rene
authors.initials: R
authors.lastname: Schweickhardt
authors.forename: Christie
authors.initials: C
authors.lastname: Kelton
authors.forename: Peter L
authors.initials: PL
authors.lastname: Ryan
authors.forename: Ross A D
authors.initials: RA
authors.lastname: Bathgate
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide; D012065:Relaxin / Q000378:metabolism
chemical_list: D007328:Insulin; C084797:Leydig insulin-like protein; D008565:Membrane Proteins; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; C417543:RXFP1 protein, human; C472867:RXFP2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D012065:Relaxin