Evidence map›Paper›PMID 26494861›Full record

ArticleMolecular pharmacology2016

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.

M Germana Sanna, Kevin P Vincent, Emanuela Repetto, Nhan Nguyen, Steven J Brown, Lusine Abgaryan, Sean W Riley, Nora B Leaf, Stuart M Cahalan, William B Kiosses and 5 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
2.1field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

28 citing papers in PubMed, 54 citations in OpenAlex.

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  12. Sphingolipid metabolism and signaling in cardiovascular diseases.Frontiers in cardiovascular medicine · 2022
    Review
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  17. Article
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  20. Sphingolipids in the Heart: From Cradle to Grave.Frontiers in endocrinology · 2020
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 3 institutions in 2 countries.

M Germana SannaDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Kevin P VincentDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Emanuela RepettoDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Nhan NguyenDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Steven J BrownDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Lusine AbgaryanDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Sean W RileyDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Nora B LeafDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Stuart M CahalanDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
William B KiossesDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Yasushi KohnoDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Joan Heller BrownDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Andrew D McCullochDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.).
Hugh RosenDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.) hrosen@scripps.edu gonzalp@scripps.edu.
Pedro J Gonzalez-CabreraDepartments of Chemical Physiology (M.G.S., E.R., N.N., H.R., P.J.G.-C.), Immunology (N.B.L.), and Molecular and Cellular Neuroscience (S.M.C.), Scripps Research Institute Molecular Screening Center (S.J.B., L.A., S.W.R.), Microscopy Core (W.B.K.), Scripps Research Institute, La Jolla, California; Kyorin Pharmaceutical Company, LTD, Tokyo, Japan (Y.K.); and Departments of Bioengineering (A.D.M., K.P.V.) and Pharmacology, University of California, San Diego, California (J.H.B.) hrosen@scripps.edu gonzalp@scripps.edu.
Scripps Research Institute · USKyorin University · JPUniversity of California, San Diego · US

Funding

UHTS Implementation(Florida)U54MH084512 · NIMH · SCRIPPS RESEARCH INSTITUTE, THE · PI DING, SHENG · 2008 to 2013
$89.2M
RhoA mediated survival signals in cardiomyocytesR37HL028143 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BROWN, JOAN HELLER · 2010 to 2019
$4.0M
Integrative Bioengineering of Heart, Vessels, and BloodT32HL105373 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHIEN, SHU, INTAGLIETTA, MARCOS · 2010 to 2019
$3.6M
Multi-scale Systems Model of Murine Heart FailureR01HL105242 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BERS, DONALD M, MCCULLOCH, ANDREW D. · 2012 to 2016
$3.5M
Optimization of S1P3 antagonists for fibrotic diseaseR01AR069877 · NIAMS · SCRIPPS RESEARCH INSTITUTE, THE · PI ROSEN, HUGH · 2016 to 2018
$1.8M
Modeling Cytosolic and Nuclear Ca2+ and IP3 Signaling in Ventricular MyocytesR03EB014593 · NIBIB · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MCCULLOCH, ANDREW D. · 2013 to 2014
$153k
NHLBI NIH HHS 1R01HL105242NHLBI NIH HHS R01 HL105242NHLBI NIH HHS R37 HL028143NHLBI NIH HHS T32 HL105373NIAMS NIH HHS R01 AR069877NIBIB NIH HHS 1R03EB014593NIBIB NIH HHS R03 EB014593NIMH NIH HHS 5U54 MH084512NIMH NIH HHS U54 MH084512
6 · The paper itself

Abstract

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.

Indexed as

AnimalsCardiotonic AgentsHeart BlockHeart RateMaleMiceMice, Inbred C57BLMice, KnockoutReceptors, LysosphingolipidSphingosine-1-Phosphate ReceptorsCardiotonic AgentsReceptors, LysosphingolipidS1pr3 protein, mouseSphingosine-1-Phosphate Receptors

Identifiers

PMID26494861
PMCPMC4702096
OpenAlexW2214593528

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.