The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7.
Glycoprotein hormone receptors, including LH receptor, FSH receptor, and TSH receptor, belong to the large G protein-coupled receptor (GPCR) superfamily but are unique in having a large ectodomain important for ligand binding. In addition to two recently isolated mammalian LGRs (leucine-rich repeat-containing, G protein-coupled receptors), LGR4 and LGR5, we further identified two new paralogs, LGR6 and LGR7, for glycoprotein hormone receptors. Phylogenetic analysis showed that there are three LGR subgroups: the known glycoprotein hormone receptors; LGR4 to 6; and a third subgroup represented by LGR7. LGR6 has a subgroup-specific hinge region after leucine-rich repeats whereas LGR7, like snail LGR, contains a low density lipoprotein (LDL) receptor cysteine-rich motif at the N terminus. Similar to LGR4 and LGR5, LGR6 and LGR7 mRNAs are expressed in multiple tissues. Although the putative ligands for LGR6 and LGR7 are unknown, studies on single amino acid mutants of LGR7, with a design based on known LH and TSH receptor gain-of-function mutations, indicated that the action of LGR7 is likely mediated by the protein kinase A but not the phospholipase C pathway. Thus, mutagenesis of conserved residues to allow constitutive receptor activation is a novel approach for the characterization of signaling pathways of selective orphan GPCRs. The present study also defines the existence of three subclasses of leucine-rich repeat-containing, G protein-coupled receptors in the human genome and allows future studies on the physiological importance of this expanding subgroup of GPCR.
Department of Gynecology and Obstetrics, Stanford University School of Medicine, California 94305-5317, USA.
S Y
SY
Hsu
M
M
Kudo
T
T
Chen
K
K
Nakabayashi
A
A
Bhalla
P J
PJ
van der Spek
M
M
van Duin
A J
AJ
Hsueh
D000595:Amino Acid Sequence; D000818:Animals; D002878:Chromosomes, Human, Pair 1; D002894:Chromosomes, Human, Pair 4; D003001:Cloning, Molecular; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008322:Mammals; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D005810:Multigene Family; D016297:Mutagenesis, Site-Directed; D010802:Phylogeny; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D011974:Receptors, LH / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
C417544:LGR6 protein, human; D008565:Membrane Proteins; C417543:RXFP1 protein, human; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011974:Receptors, LH; D018000:Receptors, Peptide; D011994:Recombinant Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins