Identification of INSL6, a New Member of the Insulin Family That Is Expressed in the Testis of the Human and Rat1

Lok, Si; Johnston, Daniel St; Conklin, Darrell; Lofton–Day, Catherine; Adams, Robyn L.; Jelmberg, A.C.; Whitmore, Theodore E.; Schrader, Sara; Griswold, Michael D.; Jaspers, Stephen R.

doi:10.1095/biolreprod62.6.1593

Cited by 116 publications

(97 citation statements)

References 20 publications

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“…5). Relaxin-3 also stimulated Ca 2ϩ mobilization in HEK293 cells co-expressing GPCR135 and G␣ 16 with an EC 50 value ϳ5 nM. HEK293 cells transfected by G␣ 16 alone did not respond to relaxin-3 stimulation.…”

Section: Characterization Of Gpcr142 By Ca 2ϩmentioning

confidence: 92%

“…Ca 2ϩ Mobilization Assays-Human embryonic kidney (HEK) 293 cells were transfected with GPCR135, GPCR142, or co-transfected with G qi5 (13) or G␣ 16 (14) expressing plasmids using LipofectAMINE. Two days after transfection, cells were detached with phosphate-buffered saline plus 10 mM EDTA.…”

Section: Methodsmentioning

confidence: 99%

“…However, when we performed similar experiments with GPCR142, no relaxin-3-stimulated Ca 2ϩ signaling was observed in HEK293 cells co-expressing GPCR142 and G qi5 (data not shown). G␣ 16 (14) has been reported to be able to couple with many GPCRs that are not normally linked to Ca 2ϩ signaling and shift their signal transduction into Ca 2ϩ signaling (17). When GPCR142 was co-expressed with G␣ 16 in HEK293 cells, relaxin-3 stimulated a strong Ca 2ϩ signal in the transfected cells in a dose-dependent manner.…”

Section: Characterization Of Gpcr142 By Ca 2ϩmentioning

confidence: 99%

“…G␣ 16 (14) has been reported to be able to couple with many GPCRs that are not normally linked to Ca 2ϩ signaling and shift their signal transduction into Ca 2ϩ signaling (17). When GPCR142 was co-expressed with G␣ 16 in HEK293 cells, relaxin-3 stimulated a strong Ca 2ϩ signal in the transfected cells in a dose-dependent manner. The EC 50 value of relaxin-3 to GPCR142 observed in the Ca 2ϩ mobilization assays is ϳ50 nM (Fig.…”

Section: Characterization Of Gpcr142 By Ca 2ϩmentioning

confidence: 99%

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Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Liu

Chen

Sutton

et al. 2003

Journal of Biological Chemistry

227

272

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We have recently identified the insulin-like peptide relaxin-3 (aka INSL7) as the endogenous ligand for an orphan G-protein-coupled receptor, GPCR135 (aka somatostatin-and angiotensin-like peptide receptor). Analysis of possible receptors related to GPCR135 revealed a single orphan receptor, GPCR142. Thus, we tested whether GPCR142 could also respond to relaxin-3 or related insulin-like molecules. Surprisingly, GPCR142 was activated by nanomolar concentrations of relaxin-3 but was completely unresponsive to all other known insulin-like peptides. We evaluated by reverse transcriptase-PCR the expression of GPCR142 mRNA in a variety of human tissues and found expression in brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid, and colon. In an analysis of other species, we were able to find a full-length mouse homolog of GPCR142, but were unable to detect any complete GPCR142 transcripts in rat. With respect to intracellular signaling, GPCR142 is similar to GPCR135 in that it potently inhibits adenylate cyclase and stimulates 35 S-GTP␥S incorporation in response to relaxin-3. However, whereas GPCR135 signaling could be converted to calcium mobilization using a G qi5 or G␣ 16 G-proteins, GPCR142 was only capable of functioning in the presence of G␣ 16 . In the accompanying article (Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C., Farmer, N., Jö rnvall, H., Sillard, R., and Lovenberg, T. W. (2003) J. Biol. Chem. 278, 50754 -50764), we present the case that relaxin-3, which has previously been shown to bind to the relaxin receptor LGR7, is most likely the endogenous ligand for GPCR135. In this report, we show an additional receptor, GPCR142, which is also selectively activated by relaxin-3. However, the anatomical localization of GPCR142 suggests that GPCR142 may have different physiological functions.Relaxin-3 (1) is a member of the insulin superfamily, where each member consists of two peptide subunits arranged by three disulfide bridges. Recently, two leucine-rich repeat-containing G-protein-coupled receptors (LGRs), 1 LGR7 and LGR8 (2, 3), have been identified as the receptors for relaxin (3-7).LGR7 and LGR8 belong to the type III hormone receptor family (follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid stimulating hormone (TSH) etc. that stimulate adenylate cyclase). Relaxin-3 was recently demonstrated to be an additional ligand for the relaxin receptor LGR7, but not LGR8 (8). Instead, the ligand INSL3 (9), another member of the insulin/relaxin family of peptides, has been shown to be an additional ligand for LGR8 (10).As part of a directed effort to identify ligands for orphan G-protein-coupled receptors (GPCRs), we established a systematic program to create tissue extracts as a source of possible GPCR ligands. In the accompanying article (23), we report the purification and identification of the peptide ligand, relaxin-3, as an endogenous ligand for orphan receptor GPCR135, aka SALPR (somatostatin-and angiotensin-like peptide receptor).In that report...

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Section: Characterization Of Gpcr142 By Ca 2ϩmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Characterization Of Gpcr142 By Ca 2ϩmentioning

confidence: 99%

Section: Characterization Of Gpcr142 By Ca 2ϩmentioning

confidence: 99%

See 2 more Smart Citations

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Liu

Chen

Sutton

et al. 2003

Journal of Biological Chemistry

227

272

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“…The A‐ and B‐chain peptides are relatively invariant within the family, and they contain highly conserved cysteine motifs. For most family members, mature hormones are processed by proteolytic cleavage of C‐peptide and signal peptide, and the A‐ and B‐chain peptides are connected by 2 interchain and 1 intrachain disulfide bonds 2, 3…”

Section: Introductionmentioning

confidence: 99%

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

Maruyama

Yoshida

et al. 2018

JAHA

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BackgroundThe insulin/insulin‐like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin‐2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin‐like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss‐of‐function and protein delivery methods.Methods and ResultsInsl6‐deficient and wild‐type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6‐knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6‐knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis‐associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol‐challenged hearts treated with INSL6 protein.ConclusionsEndogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II– and isoproterenol‐induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis.

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Ligand‐induced activation of the insulin receptor: a multi‐step process involving structural changes in both the ligand and the receptor

2009

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Current models of insulin binding to the insulin receptor (IR) propose (i) that there are two binding sites on the surface of insulin which engage with two binding sites on the receptor and (ii) that ligand binding involves structural changes in both the ligand and the receptor. Many of the features of insulin binding to its receptor, namely B-chain helix interactions with the leucine-rich repeat domain and A-chain residue interactions with peptide loops from another part of the receptor, are also seen in models of relaxin and insulin-like peptide 3 binding to their receptors. We show that these principles can likely be extended to the group of mimetic peptides described by Schäffer and coworkers, which are reported to have no sequence identity with insulin. This review summarizes our current understanding of ligand-induced activation of the IR and highlights the key issues that remain to be addressed.

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Identification of INSL6, a New Member of the Insulin Family That Is Expressed in the Testis of the Human and Rat1

Cited by 116 publications

References 20 publications

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

Ligand‐induced activation of the insulin receptor: a multi‐step process involving structural changes in both the ligand and the receptor

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