The G Protein-coupled Receptor P2Y14 Influences Insulin Release and Smooth Muscle Function in Mice*

Background: The relevance of the widely expressed GPCR P2Y14 is only partially understood. Results: Analysis of P2Y14-KO mice revealed decreased gastrointestinal emptying, reduced glucose tolerance, and insulin release. Conclusion: P2Y14 function is required for proper intestine emptying and adequate glucose response. Significance: P2Y14 plays a role in smooth muscle function and maintaining energy homeostasis by influencing insulin release. UDP sugars were identified as extracellular signaling molecules, assigning a new function to these compounds in addition to their well defined role in intracellular substrate metabolism and storage. Previously regarded as an orphan receptor, the G protein-coupled receptor P2Y14 (GPR105) was found to bind extracellular UDP and UDP sugars. Little is known about the physiological functions of this G protein-coupled receptor. To study its physiological role, we used a gene-deficient mouse strain expressing the bacterial LacZ reporter gene to monitor the physiological expression pattern of P2Y14. We found that P2Y14 is mainly expressed in pancreas and salivary glands and in subpopulations of smooth muscle cells of the gastrointestinal tract, blood vessels, lung, and uterus. Among other phenotypical differences, knock-out mice showed a significantly impaired glucose tolerance following oral and intraperitoneal glucose application. An unchanged insulin tolerance suggested altered pancreatic islet function. Transcriptome analysis of pancreatic islets showed that P2Y14 deficiency significantly changed expression of components involved in insulin secretion. Insulin secretion tests revealed a reduced insulin release from P2Y14-deficient islets, highlighting P2Y14 as a new modulator of proper insulin secretion.

• Publication year

  2014

• Venue

  Journal of Biological Chemistry

• Publication date

  2014-07-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M114.580803PMID 24993824PMCID PMC4156089
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Novel vasocontractile role of the P2Y14 receptor: characterization of its signalling in porcine isolated pancreatic arteries

  2014cited by this paper
• Purinergic P2Y₁₄ receptor modulates stress-induced hematopoietic stem/progenitor cell senescence.

  2014cited by this paper
• The purinergic P2Y14 receptor axis is a molecular determinant for organism survival under in utero radiation toxicity

  2013cited by this paper
• An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans.

  2013influential reference
• G protein-coupled receptor deorphanizations.

  2013cited by this paper
• Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks

  2012cited by this paper
• GPR105 Ablation Prevents Inflammation and Improves Insulin Sensitivity in Mice with Diet-Induced Obesity

  2012influential reference
• Identification of novel transcripts in annotated genomes using RNA-Seq

  2011cited by this paper
• Reduced Food Intake and Body Weight in Mice Deficient for the G Protein-Coupled Receptor GPR82

  2011cited by this paper
• Understanding Molecular Recognition by G protein βγ Subunits on the Path to Pharmacological Targeting

  2011cited by this paper
• Discovery of Novel P2Y14 Agonist and Antagonist Using Conventional and Nonconventional Methods

  2011cited by this paper
• Integrating diverse genomic data using gene sets

  2011cited by this paper
• MafA and MafB activity in pancreatic β cells.

  2011cited by this paper
• NTPDase1 (CD39) controls nucleotide-dependent vasoconstriction in mouse.

  2010cited by this paper
• Exposure to mycotoxins increases the allergic immune response in a murine asthma model.

  2010cited by this paper
• C-kit-immunopositive interstitial cells of Cajal in human embryonal and fetal oesophagus

  2010cited by this paper
• The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice.

  2010cited by this paper
• UDP‐glucose acting at P2Y14 receptors is a mediator of mast cell degranulation

  2010influential reference
• Gi- and Gq-coupled ADP (P2Y) receptors act in opposition to modulate nociceptive signaling and inflammatory pain behavior

  2010cited by this paper
• Ca2+ signalling by P2Y receptors in cultured rat aortic smooth muscle cells

  2010cited by this paper
• Deconvolution of complex G protein–coupled receptor signaling in live cells using dynamic mass redistribution measurements

  2010cited by this paper
• M3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1

  2010cited by this paper
• Galanin, galanin receptors, and drug targets.

  2010cited by this paper
• Differential expression analysis for sequence count data

  2010cited by this paper
• A new collagenase blend increases the number of islets isolated from mouse pancreas

  2009cited by this paper
• ToppGene Suite for gene list enrichment analysis and candidate gene prioritization

  2009influential reference
• UDP-glucose modulates gastric function through P2Y14 receptor-dependent and -independent mechanisms.

  2009cited by this paper
• Quantification of Gi-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y14 Receptor

  2009cited by this paper
• Regulation of insulin secretion: a matter of phase control and amplitude modulation

  2009influential reference
• G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction.

  2009cited by this paper
• Deletion of GPR40 Impairs Glucose-Induced Insulin Secretion In Vivo in Mice Without Affecting Intracellular Fuel Metabolism in Islets

  2009cited by this paper
• Luciferase activity under direct ligand-dependent control of a muscarinic acetylcholine receptor

  2009cited by this paper
• Galanin – 25 years with a multitalented neuropeptide

  2008cited by this paper
• Structural and functional evolution of the P2Y12-like receptor group

  2007cited by this paper
• Neurons and glial cells differentially express P2Y receptor mRNAs in the rat dorsal root ganglion and spinal cord

  2006cited by this paper
• Structure and organization of interstitial cells of Cajal in the gastrointestinal tract

  2006cited by this paper
• Functional expression of the P2Y14 receptor in human neutrophils.

  2006cited by this paper
• Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas.

  2006cited by this paper
• MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells.

  2006cited by this paper
• MafB: An Activator of the Glucagon Gene Expressed in Developing Islet α- and β-Cells

  2006cited by this paper
• Pharmacological effects mediated by UDP-glucose that are independent of P2Y14 receptor expression.

  2005cited by this paper
• Functional expression of the P2Y14 receptor in murine T‐lymphocytes

  2005cited by this paper
• Ca(2+)-induced Ca(2+) release via inositol 1,4,5-trisphosphate receptors is amplified by protein kinase A and triggers exocytosis in pancreatic beta-cells.

  2004cited by this paper
• Functional expression of human and mouse P2Y12 receptors in Saccharomyces cerevisiae.

  2004cited by this paper
• Ca2+-induced Ca2+ Release via Inositol 1,4,5-trisphosphate Receptors Is Amplified by Protein Kinase A and Triggers Exocytosis in Pancreatic β-Cells*

  2004cited by this paper
• Muscarinic stimulation of pancreatic insulin and glucagon release is abolished in m3 muscarinic acetylcholine receptor-deficient mice.

  2004cited by this paper
• Enhancing incretin action for the treatment of type 2 diabetes.

  2003cited by this paper
• P2Y-like receptor, GPR105 (P2Y14), identifies and mediates chemotaxis of bone-marrow hematopoietic stem cells.

  2003cited by this paper
• GPR105, a novel Gi/o-coupled UDP-glucose receptor expressed on brain glia and peripheral immune cells, is regulated by immunologic challenge: possible role in neuroimmune function.

  2003cited by this paper
• Human Immature Monocyte-Derived Dendritic Cells Express the G Protein-Coupled Receptor GPR105 (KIAA0001, P2Y14) and Increase Intracellular Calcium in Response to its Agonist, Uridine Diphosphoglucose

  2003influential reference
• The Structural Evolution of a P2Y-like G-protein-coupled Receptor*

  2003cited by this paper
• Insulin signalling and the regulation of glucose and lipid metabolism

  2001cited by this paper
• Cloning, pharmacology, and tissue distribution of G-protein-coupled receptor GPR105 (KIAA0001) rodent orthologs.

  2001cited by this paper
• A G Protein-coupled Receptor for UDP-glucose*

  2000cited by this paper
• Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice.

  2000cited by this paper
• Ultrastructural and histochemical characterization of special muscle cells in the monkey small intestine.

  2000cited by this paper
• The Calcium/Calmodulin-dependent Phosphodiesterase PDE1C Down-regulates Glucose-induced Insulin Secretion*

  1999cited by this paper
• The isolation and characterization of a novel G protein-coupled receptor regulated by immunologic challenge.

  1997cited by this paper
• Factors determining the glucose sensitivity and glucose responsiveness of pancreatic beta cells.

  1996cited by this paper
• Heterogeneity in Pancreatic β-cell Population

  1992cited by this paper

• SLC35 Transporters: The Missing Link Between Glycosylation and Type 2 Diabetes

  2026cites this paper
• Metabolomic Insights Into the Impact of a Maternal Western‐Style Diet and Leptin Supplementation During Suckling on Adult Rat Offspring

  2026cites this paper
• Discovery of a series of novel 3-sulfonamido benzoic acid derivatives as promising P2Y14R antagonists for acute lung injury.

  2025cites this paper
• P2Y14R activation facilitates liver regeneration via CREB/DNMT3b/Dact-2/β-Catenin signals in acute liver failure

  2025cites this paper
• Cell‐Specific Functions of the BAI/ADGRB Subfamily of Adhesion G‐Protein Coupled Receptors

  2025cites this paper
• UDP-glucose Regulates Dendritic Cell Mitochondrial Respiration via a Nitric Oxide-Dependent Mechanism.

  2025cites this paper
• The adhesion GPCR GPR116/ADGRF5 has a dual function in pancreatic islets regulating somatostatin release and islet development

  2024cites this paper
• NF1-dependent disruption of the blood-nerve-barrier is improved by blockade of P2RY14

  2024cites this paper
• Using integrated transcriptomics and metabolomics to explore the effects of infant formula on the growth and development of small intestinal organoids.

  2024cites this paper
• Establishing immortalized brown and white preadipocyte cell lines from young and aged mice

  2024cites this paper
• Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG

  2024cites this paper
• A Systematic Review of the Role of Purinergic Signalling Pathway in the Treatment of COVID-19

  2023cites this paper
• Purinergic Signaling and its Role in the Stem Cell Differentiation.

  2023cites this paper
• Pharmacological characterization of P2Y receptor subtypes – an update

  2023cites this paper
• Reduced urine volume and changed renal sphingolipid metabolism in P2ry14-deficient mice

  2023influential citation
• A homozygous truncating mutation of FGL2 is associated with immune dysregulation.

  2022cites this paper
• G protein-coupled receptors as regulators of pancreatic islet functionality.

  2022cites this paper
• The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

  2022cites this paper
• Purinergic receptors modulators: An emerging pharmacological tool for disease management

  2022cites this paper
• The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver

  2022cites this paper
• The clinical impact of maternal weight on offspring health: lights and shadows in breast milk metabolome

  2021cites this paper
• Targeting Islet GPCRs to Improve Insulin Secretion

  2021cites this paper
• The relevance of adhesion G protein-coupled receptors in metabolic functions

  2021influential citation
• Obesity-induced changes in human islet G protein-coupled receptor expression: Implications for metabolic regulation.

  2021cites this paper
• Design, synthesis and evaluation of 3-amide-5-aryl benzoic acid derivatives as novel P2Y14R antagonists with potential high efficiency against acute gouty arthritis.

  2021cites this paper
• Inhibitory effect of UDP-glucose on cAMP generation and insulin secretion

  2020influential citation
• Knockout and Knock-in Mouse Models to Study Purinergic Signaling.

  2020cites this paper
• Exploring G Protein-Coupled Receptor Signaling in Primary Pancreatic Islets

  2020cites this paper
• Glycogen metabolism regulates macrophage-mediated acute inflammatory responses

  2020cites this paper
• P2Y14 Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model.

  2020cites this paper
• Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

  2020cites this paper
• The Human Breast Milk Metabolome in Overweight and Obese Mothers

  2020cites this paper
• Exploration of Alternative Scaffolds for P2Y14 Receptor Antagonists Containing a Biaryl Core.

  2020cites this paper
• Molecular Pharmacology of P2Y Receptor Subtypes.

  2020cites this paper
• New small molecule fluorescent probes for G protein-coupled receptors: valuable tools for drug discovery.

  2020cites this paper
• Recent progress on the discovery of P2Y14 receptor antagonists.

  2019cites this paper
• Involvement of the Adhesion GPCRs Latrophilins in the Regulation of Insulin Release.

  2019cites this paper
• Pharmacology of P2Y receptors.

  2019cites this paper
• Design, synthesis and anti-inflammatory evaluation of 3-amide benzoic acid derivatives as novel P2Y14 receptor antagonists.

  2019cites this paper
• The expanding functional roles and signaling mechanisms of adhesion G protein–coupled receptors

  2019cites this paper
• Tools and drugs for uracil nucleotide‐activated P2Y receptors

  2018cites this paper
• ATP mediates a negative autocrine signal on stimulus-secretion coupling in mouse pancreatic β-cells

  2018cites this paper
• G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

  2018cites this paper
• Gene expression profiles of ion channels and receptors in mouse resistance arteries: Effects of cell type, vascular bed, and age

  2018cites this paper
• UDP-sugars activate P2Y14 receptors to mediate vasoconstriction of the porcine coronary artery

  2017cites this paper
• P2Y Receptors in Immune Response and Inflammation.

  2017cites this paper
• Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists

  2016cites this paper
• Pharmacology and structure of P2Y receptors.

  2016cites this paper
• Role of the P2Y1 receptor in platelet activation

  2016cites this paper
• Comments on Methods to Suppress Endogenous β-Galactosidase Activity in Mouse Tissues Expressing the LacZ Reporter Gene

  2016cites this paper
• Design, synthesis, pharmacological characterization of a fluorescent agonist of the P2Y₁₄ receptor.

  2015cites this paper
• UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y14 Receptor Activation

  2015influential citation
• 3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling.

  2015cites this paper
• FFAR3 modulates insulin secretion and global gene expression in mouse islets

  2015cites this paper
• Local Purinergic Control of Arteriolar Reactivity in Pancreatic Islets and Renal Glomeruli

  2014cites this paper
• Novel Insulin Receptor-Signaling Platform

  2014cites this paper