Murine GPRC6A Mediates Cellular Responses to L-Amino Acids, but Not Osteocalcin Variants.
Identifieur interne : 002328 ( PubMed/Curation ); précédent : 002327; suivant : 002329Murine GPRC6A Mediates Cellular Responses to L-Amino Acids, but Not Osteocalcin Variants.
Auteurs : Patricia Rueda [Australie] ; Elizabeth Harley [France] ; Yao Lu [Australie] ; Gregory D. Stewart [Australie] ; Stewart Fabb [Australie] ; Natalie Diepenhorst [Australie] ; Béatrice Cremers [France] ; Marie-Hélène Rouillon [France] ; Isabelle Wehrle [France] ; Anne Geant [France] ; Gwladys Lamarche [France] ; Katie Leach [Australie] ; William N. Charman [Australie] ; Arthur Christopoulos [Australie] ; Roger J. Summers [Australie] ; Patrick M. Sexton [Australie] ; Christopher J. Langmead [Australie]Source :
- PloS one [ 1932-6203 ] ; 2016.
Descripteurs français
- KwdFr :
- MESH :
- métabolisme : Cellules à insuline, Glucagon-like peptide 1, Insuline, Récepteurs couplés aux protéines G.
- pharmacologie : Acides aminés, Ostéocalcine.
- Animaux, Cellules HEK293, Cellules à insuline, Humains, Liaison aux protéines, Souris.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Glucagon-Like Peptide 1, Insulin, Receptors, G-Protein-Coupled.
- chemical , pharmacology : Amino Acids, Osteocalcin.
- drug effects : Insulin-Secreting Cells.
- metabolism : Insulin-Secreting Cells.
- Animals, HEK293 Cells, Humans, Mice, Protein Binding.
Abstract
Phenotyping of Gprc6a KO mice has shown that this promiscuous class C G protein coupled receptor is variously involved in regulation of metabolism, inflammation and endocrine function. Such effects are described as mediated by extracellular calcium, L-amino acids, the bone-derived peptide osteocalcin (OCN) and the male hormone testosterone, introducing the concept of a bone-energy-metabolism-reproduction functional crosstalk mediated by GPRC6A. However, whilst the calcium and L-amino acid-sensing properties of GPRC6A are well established, verification of activity of osteocalcin at both human and mouse GPRC6A in vitro has proven somewhat elusive. This study characterises the in vitro pharmacology of mouse GPRC6A in response to its putative ligands in both recombinant and endogenous GPRC6A-expressing cells. Using cell signalling, and glucagon-like peptide (GLP)-1 and insulin release assays, our results confirm that basic L-amino acids act as agonists of the murine GPRC6A receptor in both recombinant cells and immortalised entero-endocrine and pancreatic β-cells. In contrast, our studies do not support a role for OCN as a direct ligand for mouse GPRC6A, suggesting that the reported in vivo effects of OCN that require GPRC6A may be indirect, rather than via direct activation of the receptor.
DOI: 10.1371/journal.pone.0146846
PubMed: 26785252
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<term>HEK293 Cells</term>
<term>Humans</term>
<term>Insulin (metabolism)</term>
<term>Insulin-Secreting Cells (drug effects)</term>
<term>Insulin-Secreting Cells (metabolism)</term>
<term>Mice</term>
<term>Osteocalcin (pharmacology)</term>
<term>Protein Binding</term>
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<term>Animaux</term>
<term>Cellules HEK293</term>
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<term>Cellules à insuline (métabolisme)</term>
<term>Glucagon-like peptide 1 (métabolisme)</term>
<term>Humains</term>
<term>Insuline (métabolisme)</term>
<term>Liaison aux protéines</term>
<term>Ostéocalcine (pharmacologie)</term>
<term>Récepteurs couplés aux protéines G (métabolisme)</term>
<term>Souris</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glucagon-Like Peptide 1</term>
<term>Insulin</term>
<term>Receptors, G-Protein-Coupled</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Amino Acids</term>
<term>Osteocalcin</term>
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</keywords>
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<term>Glucagon-like peptide 1</term>
<term>Insuline</term>
<term>Récepteurs couplés aux protéines G</term>
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<term>Ostéocalcine</term>
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<term>HEK293 Cells</term>
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<term>Cellules HEK293</term>
<term>Cellules à insuline</term>
<term>Humains</term>
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<front><div type="abstract" xml:lang="en">Phenotyping of Gprc6a KO mice has shown that this promiscuous class C G protein coupled receptor is variously involved in regulation of metabolism, inflammation and endocrine function. Such effects are described as mediated by extracellular calcium, L-amino acids, the bone-derived peptide osteocalcin (OCN) and the male hormone testosterone, introducing the concept of a bone-energy-metabolism-reproduction functional crosstalk mediated by GPRC6A. However, whilst the calcium and L-amino acid-sensing properties of GPRC6A are well established, verification of activity of osteocalcin at both human and mouse GPRC6A in vitro has proven somewhat elusive. This study characterises the in vitro pharmacology of mouse GPRC6A in response to its putative ligands in both recombinant and endogenous GPRC6A-expressing cells. Using cell signalling, and glucagon-like peptide (GLP)-1 and insulin release assays, our results confirm that basic L-amino acids act as agonists of the murine GPRC6A receptor in both recombinant cells and immortalised entero-endocrine and pancreatic β-cells. In contrast, our studies do not support a role for OCN as a direct ligand for mouse GPRC6A, suggesting that the reported in vivo effects of OCN that require GPRC6A may be indirect, rather than via direct activation of the receptor.</div>
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<ArticleTitle>Murine GPRC6A Mediates Cellular Responses to L-Amino Acids, but Not Osteocalcin Variants.</ArticleTitle>
<Pagination><MedlinePgn>e0146846</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pone.0146846</ELocationID>
<Abstract><AbstractText>Phenotyping of Gprc6a KO mice has shown that this promiscuous class C G protein coupled receptor is variously involved in regulation of metabolism, inflammation and endocrine function. Such effects are described as mediated by extracellular calcium, L-amino acids, the bone-derived peptide osteocalcin (OCN) and the male hormone testosterone, introducing the concept of a bone-energy-metabolism-reproduction functional crosstalk mediated by GPRC6A. However, whilst the calcium and L-amino acid-sensing properties of GPRC6A are well established, verification of activity of osteocalcin at both human and mouse GPRC6A in vitro has proven somewhat elusive. This study characterises the in vitro pharmacology of mouse GPRC6A in response to its putative ligands in both recombinant and endogenous GPRC6A-expressing cells. Using cell signalling, and glucagon-like peptide (GLP)-1 and insulin release assays, our results confirm that basic L-amino acids act as agonists of the murine GPRC6A receptor in both recombinant cells and immortalised entero-endocrine and pancreatic β-cells. In contrast, our studies do not support a role for OCN as a direct ligand for mouse GPRC6A, suggesting that the reported in vivo effects of OCN that require GPRC6A may be indirect, rather than via direct activation of the receptor.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rueda</LastName>
<ForeName>Patricia</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Harley</LastName>
<ForeName>Elizabeth</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>Institut de Recherches Servier, Suresnes, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lu</LastName>
<ForeName>Yao</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Stewart</LastName>
<ForeName>Gregory D</ForeName>
<Initials>GD</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Fabb</LastName>
<ForeName>Stewart</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Diepenhorst</LastName>
<ForeName>Natalie</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cremers</LastName>
<ForeName>Béatrice</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>Institut de Recherches Servier, Suresnes, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rouillon</LastName>
<ForeName>Marie-Hélène</ForeName>
<Initials>MH</Initials>
<AffiliationInfo><Affiliation>Institut de Recherches Servier, Suresnes, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wehrle</LastName>
<ForeName>Isabelle</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>Institut de Recherches Servier, Suresnes, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Geant</LastName>
<ForeName>Anne</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Institut de Recherches Servier, Suresnes, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lamarche</LastName>
<ForeName>Gwladys</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Institut de Recherches Servier, Suresnes, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Leach</LastName>
<ForeName>Katie</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Charman</LastName>
<ForeName>William N</ForeName>
<Initials>WN</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Christopoulos</LastName>
<ForeName>Arthur</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Summers</LastName>
<ForeName>Roger J</ForeName>
<Initials>RJ</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sexton</LastName>
<ForeName>Patrick M</ForeName>
<Initials>PM</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Langmead</LastName>
<ForeName>Christopher J</ForeName>
<Initials>CJ</Initials>
<AffiliationInfo><Affiliation>Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2016</Year>
<Month>01</Month>
<Day>19</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>PLoS One</MedlineTA>
<NlmUniqueID>101285081</NlmUniqueID>
<ISSNLinking>1932-6203</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000596">Amino Acids</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C515750">GPRC6A protein, mouse</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D007328">Insulin</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D043562">Receptors, G-Protein-Coupled</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>104982-03-8</RegistryNumber>
<NameOfSubstance UI="D015675">Osteocalcin</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>89750-14-1</RegistryNumber>
<NameOfSubstance UI="D052216">Glucagon-Like Peptide 1</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
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<MeshHeadingList><MeshHeading><DescriptorName UI="D000596" MajorTopicYN="N">Amino Acids</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D052216" MajorTopicYN="N">Glucagon-Like Peptide 1</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D057809" MajorTopicYN="N">HEK293 Cells</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D007328" MajorTopicYN="N">Insulin</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D050417" MajorTopicYN="N">Insulin-Secreting Cells</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015675" MajorTopicYN="N">Osteocalcin</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011485" MajorTopicYN="N">Protein Binding</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D043562" MajorTopicYN="N">Receptors, G-Protein-Coupled</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
</MeshHeadingList>
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