{"id":{"repo_id":"dundee","oai_identifier":"oai:discovery.dundee.ac.uk:studenttheses/497e5c51-1d7f-48e1-b8c8-ca698109e234"},"canonical_url":"https://search.dev.ndltd.org/etd/dundee/oai:discovery.dundee.ac.uk:studenttheses/497e5c51-1d7f-48e1-b8c8-ca698109e234","repository":{"repo_id":"dundee","name":"University of Dundee","base_url":"https://discovery.dundee.ac.uk/ws/oai"},"display":{"title":"Lipid sensitivity of the GPR132 receptor","abstract":"The pH sensitive receptors are a group of four phylogenetically related G protein coupled receptors (GPCRs). The prototypical member of this family, GPR68, is activated by low pH extracellular conditions. However, GPR132 does not contain histidine residues at equivalent positions and is likely not to be activated by acid. GPR132 is described by the International Union of Basic and Clinical Pharmacology (IUPHAR) as an orphan GPCR, although there have been several reports linking it to activation by lipid molecules.<br/><br/>GPR132 has been linked to the pathologies of inflammation, nociception and cancer. Therefore, an understanding of the molecular mechanisms which regulate this receptor is important to be able to devise strategies to restore homeostasis and alleviate disease. <br/><br/>This study utilises different cell based assay platforms to demonstrate activation of GPR132 by two distinct groups of endogenous lipid; oxidised free fatty acid and N-acyl glycine. Both groups are found to activate GPR132 mediated downstream signalling pathways at varying magnitudes, perhaps explaining the different biological activities of these separate molecular families. Further computational modelling were used to identify a binding site for these ligands and validated using receptor mutagenesis. Interestingly, mutation of a highly conserved residue on transmembrane domain 5 was found to switch full agonist behaviour of a synthetic ligand towards an inverse agonist. Altogether, the experiments outlined in this thesis may prove useful in the design of potent antagonists for this receptor.","abstract_html":"The pH sensitive receptors are a group of four phylogenetically related G protein coupled receptors (GPCRs). The prototypical member of this family, GPR68, is activated by low pH extracellular conditions. However, GPR132 does not contain histidine residues at equivalent positions and is likely not to be activated by acid. GPR132 is described by the International Union of Basic and Clinical Pharmacology (IUPHAR) as an orphan GPCR, although there have been several reports linking it to activation by lipid molecules.&lt;br/&gt;&lt;br/&gt;GPR132 has been linked to the pathologies of inflammation, nociception and cancer. Therefore, an understanding of the molecular mechanisms which regulate this receptor is important to be able to devise strategies to restore homeostasis and alleviate disease. &lt;br/&gt;&lt;br/&gt;This study utilises different cell based assay platforms to demonstrate activation of GPR132 by two distinct groups of endogenous lipid; oxidised free fatty acid and N-acyl glycine. Both groups are found to activate GPR132 mediated downstream signalling pathways at varying magnitudes, perhaps explaining the different biological activities of these separate molecular families. Further computational modelling were used to identify a binding site for these ligands and validated using receptor mutagenesis. Interestingly, mutation of a highly conserved residue on transmembrane domain 5 was found to switch full agonist behaviour of a synthetic ligand towards an inverse agonist. Altogether, the experiments outlined in this thesis may prove useful in the design of potent antagonists for this receptor.","abstract_has_math":false,"creators":["Foster, James Rhys"],"institution":"University of Dundee","degree_name":"Doctor of Philosophy","degree_level":"Doctoral Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Harvey, Jenni"],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019","date_published":"2019","updated_at":"2026-07-24T02:08:46Z","subjects":[],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:discovery.dundee.ac.uk:studenttheses/497e5c51-1d7f-48e1-b8c8-ca698109e234"],"render_values":[{"text":"oai:discovery.dundee.ac.uk:studenttheses/497e5c51-1d7f-48e1-b8c8-ca698109e234","href":null,"code":true}]}]},"links":{"outbound_url":"https://discovery.dundee.ac.uk/en/studentTheses/497e5c51-1d7f-48e1-b8c8-ca698109e234","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Harvey, Jenni"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Biotechnology and Biological Sciences Research Council","GlaxoSmithKline"]},{"key":"dc:creator","label":"Author","values":["Foster, James Rhys"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019"]},{"key":"dc:date.issued","label":"Date","values":["2019"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Systems Medicine"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Dundee"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://discovery.dundee.ac.uk/en/studentTheses/497e5c51-1d7f-48e1-b8c8-ca698109e234"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral Thesis"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2024-05-31"]},{"key":"dc:rights.embargoreason","label":"Dc Rights Embargoreason","values":["/dk/atira/pure/core/document/studentthesisembargoreason/content_contains_confidential_information"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:discovery.dundee.ac.uk:studenttheses/497e5c51-1d7f-48e1-b8c8-ca698109e234","https://discovery.dundee.ac.uk/en/studentTheses/497e5c51-1d7f-48e1-b8c8-ca698109e234"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://discovery.dundee.ac.uk/files/34181171/THESISfinal_Redacted.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The pH sensitive receptors are a group of four phylogenetically related G protein coupled receptors (GPCRs). The prototypical member of this family, GPR68, is activated by low pH extracellular conditions. However, GPR132 does not contain histidine residues at equivalent positions and is likely not to be activated by acid. GPR132 is described by the International Union of Basic and Clinical Pharmacology (IUPHAR) as an orphan GPCR, although there have been several reports linking it to activation by lipid molecules.<br/><br/>GPR132 has been linked to the pathologies of inflammation, nociception and cancer. Therefore, an understanding of the molecular mechanisms which regulate this receptor is important to be able to devise strategies to restore homeostasis and alleviate disease. <br/><br/>This study utilises different cell based assay platforms to demonstrate activation of GPR132 by two distinct groups of endogenous lipid; oxidised free fatty acid and N-acyl glycine. Both groups are found to activate GPR132 mediated downstream signalling pathways at varying magnitudes, perhaps explaining the different biological activities of these separate molecular families. Further computational modelling were used to identify a binding site for these ligands and validated using receptor mutagenesis. Interestingly, mutation of a highly conserved residue on transmembrane domain 5 was found to switch full agonist behaviour of a synthetic ligand towards an inverse agonist. Altogether, the experiments outlined in this thesis may prove useful in the design of potent antagonists for this receptor."]},{"key":"dc:title","label":"Title","values":["Lipid sensitivity of the GPR132 receptor"]}]}],"canonical_facts":{"dc:contributor.advisor":["Harvey, Jenni"],"dc:contributor.sponsor":["Biotechnology and Biological Sciences Research Council","GlaxoSmithKline"],"dc:creator":["Foster, James Rhys"],"dc:date":["2019"],"dc:date.issued":["2019"],"dc:description.abstract":["The pH sensitive receptors are a group of four phylogenetically related G protein coupled receptors (GPCRs). The prototypical member of this family, GPR68, is activated by low pH extracellular conditions. However, GPR132 does not contain histidine residues at equivalent positions and is likely not to be activated by acid. GPR132 is described by the International Union of Basic and Clinical Pharmacology (IUPHAR) as an orphan GPCR, although there have been several reports linking it to activation by lipid molecules.<br/><br/>GPR132 has been linked to the pathologies of inflammation, nociception and cancer. Therefore, an understanding of the molecular mechanisms which regulate this receptor is important to be able to devise strategies to restore homeostasis and alleviate disease. <br/><br/>This study utilises different cell based assay platforms to demonstrate activation of GPR132 by two distinct groups of endogenous lipid; oxidised free fatty acid and N-acyl glycine. Both groups are found to activate GPR132 mediated downstream signalling pathways at varying magnitudes, perhaps explaining the different biological activities of these separate molecular families. Further computational modelling were used to identify a binding site for these ligands and validated using receptor mutagenesis. 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