{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T08:34:23Z","timestamp":1767170063776,"version":"build-2238731810"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,4,25]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Both \u03b2-adrenergic receptor (\u03b2-AR) and G\n                      <jats:sub>q<\/jats:sub>\n                      -coupled receptor (G\n                      <jats:sub>q<\/jats:sub>\n                      R) agonist\u2013driven signaling play key roles in the events, leading up to and during cardiac dysfunction. How these stimuli interact at the level of protein kinase D (PKD), a nodal point in cardiac hypertrophic signaling, remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      To assess the spatiotemporal dynamics of PKD activation in response to \u03b2-AR signaling alone and on coactivation with G\n                      <jats:sub>q<\/jats:sub>\n                      R-agonists. This will test our hypothesis that compartmentalized PKD signaling reconciles disparate findings of PKA facilitation and inhibition of PKD activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      We report on the spatial and temporal profiles of PKD activation using green fluorescent protein-tagged PKD (wildtype or mutant S427E) and targeted fluorescence resonance energy transfer\u2013based biosensors (D-kinase activity reporters) in adult cardiomyocytes. We find that \u03b2-AR\/PKA signaling drives local nuclear activation of PKD, without preceding sarcolemmal translocation. We also discover pronounced interference of \u03b2-AR\/cAMP\/PKA signaling on G\n                      <jats:sub>q<\/jats:sub>\n                      R-induced translocation and activation of PKD throughout the cardiomyocyte. We attribute these effects to direct, PKA-dependent phosphorylation of PKD-S427. We also show that phosphomimetic substitution of S427 likewise impedes G\n                      <jats:sub>q<\/jats:sub>\n                      R-induced PKD translocation and activation. In neonatal myocytes, S427E inhibits G\n                      <jats:sub>q<\/jats:sub>\n                      R-evoked cell growth and expression of hypertrophic markers. Finally, we show altered S427 phosphorylation in transverse aortic constriction\u2013induced hypertrophy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      \u03b2-AR signaling triggers local nuclear signaling and inhibits G\n                      <jats:sub>q<\/jats:sub>\n                      R-mediated PKD activation by preventing its intracellular translocation. PKA-dependent phosphorylation of PKD-S427 fine-tunes the PKD responsiveness to G\n                      <jats:sub>q<\/jats:sub>\n                      R-agonists, serving as a key integration point for \u03b2-adrenergic and G\n                      <jats:sub>q<\/jats:sub>\n                      -coupled stimuli.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.114.303870","type":"journal-article","created":{"date-parts":[[2014,3,19]],"date-time":"2014-03-19T00:55:30Z","timestamp":1395190530000},"page":"1398-1409","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["\u03b2-Adrenergic Signaling Inhibits G\n                    <sub>q<\/sub>\n                    -Dependent Protein Kinase D Activation by Preventing Protein Kinase D Translocation"],"prefix":"10.1161","volume":"114","author":[{"given":"C. Blake","family":"Nichols","sequence":"first","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Wei","family":"Chang","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maura","family":"Ferrero","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brent M.","family":"Wood","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew L.","family":"Stein","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda J.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derrick","family":"Ha","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert R.","family":"Rigor","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sven","family":"Bossuyt","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto University School of Science and Technology, Helsinki, Finland (S.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Bossuyt","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis (C.B.N., C.-W.C., M.F., B.M.W., M.L.S., A.J.F., D.H., R.R.R., J.B.); Department of Physiology, Loyola University Chicago, Maywood, IL (C.-W.C.); and School of Engineering, Department of Engineering Design and Production, Aalto 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