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Collective and Coordinated Conformational Changes Determine Agonism or Antagonism at the Human Trace Amine-Associated Receptor 1.

ABSTRACT: The human trace amine-associated receptor (hTAAR1), a G protein-coupled receptor, has been postulated as a new target in the treatment of neuropsychiatric conditions. The mechanism associated with activation or inactivation by agonists or antagonists in hTAAR1 and other GPCRs has not yet been fully elucidated. In this study, we combined computational methods including homology modeling, docking, and molecular dynamic simulations to reveal novel conformational changes associated with agonist and antagonist interactions in hTAAR1. Our findings suggest a differential cascade of coordinated movements based on the presence of either an agonist or antagonist and primarily involving the second extracellular loop, transmembrane domain 5, and the third intracellular domains of hTAAR1. Our study provides an opportunity to predict the effects on new ligands with agonistic or antagonistic activity at hTAAR1 based on the reported conformational changes.

SUBMITTER: Robles AI

PROVIDER: S-EPMC10652269 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Collective and Coordinated Conformational Changes Determine Agonism or Antagonism at the Human Trace Amine-Associated Receptor 1.

Robles Agustín I AI Dinamarca-Villarroel Luis L Torres Gonzalo E GE Fierro Angélica A

ACS omega 20231031 45

The human trace amine-associated receptor (hTAAR1), a G protein-coupled receptor, has been postulated as a new target in the treatment of neuropsychiatric conditions. The mechanism associated with activation or inactivation by agonists or antagonists in hTAAR1 and other GPCRs has not yet been fully elucidated. In this study, we combined computational methods including homology modeling, docking, and molecular dynamic simulations to reveal novel conformational changes associated with agonist and ...[more]

PMID: 38024694

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Project description:ObjectiveTreatment with glucagon receptor antagonists (GRAs) reduces blood glucose but causes dyslipidemia and accumulation of fat in the liver. We investigated the acute and chronic effects of glucagon on lipid metabolism in mice.MethodsChronic effects of glucagon receptor signaling on lipid metabolism were studied using oral lipid tolerance tests (OLTTs) in overnight fasted glucagon receptor knockout (Gcgr-/-) mice, and in C57Bl/6JRj mice treated with a glucagon receptor antibody (GCGR Ab) or a long-acting glucagon analogue (GCGA) for eight weeks. Following treatment, liver tissue was harvested for RNA-sequencing and triglyceride measurements. Acute effects were studied in C57Bl/6JRj mice treated with a GRA or GCGA 1 h or immediately before OLTTs, respectively. Direct effects of glucagon on hepatic lipolysis were studied using isolated perfused mouse liver preparations. To investigate potential effects of GCGA and GRA on gastric emptying, paracetamol was, in separate experiments, administered immediately before OLTTs.ResultsPlasma triglyceride concentrations increased 2-fold in Gcgr-/- mice compared to their wild-type littermates during the OLTT (P = 0.001). Chronic treatment with GCGR Ab increased, whereas GCGA treatment decreased, plasma triglyceride concentrations during OLTTs (P < 0.05). Genes involved in lipid metabolism were upregulated upon GCGR Ab treatment while GCGA treatment had opposite effects. Acute GRA and GCGA treatment, respectively, increased (P = 0.02) and decreased (P = 0.003) plasma triglyceride concentrations during OLTTs. Glucagon stimulated hepatic lipolysis, evident by an increase in free fatty acid concentrations in the effluent from perfused mouse livers. In line with this, GCGR Ab treatment increased, while GCGA treatment decreased, liver triglyceride concentrations. The effects of glucagon appeared independent of changes in gastric emptying of paracetamol.ConclusionsGlucagon receptor signaling regulates triglyceride metabolism, both chronically and acutely, in mice. These data expand glucagon´s biological role and implicate that intact glucagon signaling is important for lipid metabolism. Glucagon agonism may have beneficial effects on hepatic and peripheral triglyceride metabolism.

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Collective and Coordinated Conformational Changes Determine Agonism or Antagonism at the Human Trace Amine-Associated Receptor 1.

Publications

Collective and Coordinated Conformational Changes Determine Agonism or Antagonism at the Human Trace Amine-Associated Receptor 1.

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