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http://purl.uniprot.org/citations/26494861http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26494861http://www.w3.org/2000/01/rdf-schema#comment"The molecular pharmacology of the G protein-coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P3-knockin and S1P3-knockout mice to define the spatial and functional properties of S1P3 in regulating cardiac conduction. We show that S1P3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P3-knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P3-mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.org/dc/terms/identifier"doi:10.1124/mol.115.100222"xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Sanna M.G."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Nguyen N."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Brown S.J."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Rosen H."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Kohno Y."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Brown J.H."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Kiosses W.B."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Cahalan S.M."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"McCulloch A.D."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Gonzalez-Cabrera P.J."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Repetto E."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Leaf N.B."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Abgaryan L."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Riley S.W."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/author"Vincent K.P."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/name"Mol Pharmacol"xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/pages"176-186"xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/title"Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction."xsd:string
http://purl.uniprot.org/citations/26494861http://purl.uniprot.org/core/volume"89"xsd:string
http://purl.uniprot.org/citations/26494861http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/26494861
http://purl.uniprot.org/citations/26494861http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/26494861
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