{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:00:20Z","timestamp":1787500820975,"version":"build-2736575974"},"reference-count":14,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2011,7,22]]},"abstract":"\n \n Rationale:<\/jats:underline>\n <\/jats:title>\n \n L-type Ca\n 2+<\/jats:sup>\n (Ca\n V<\/jats:sub>\n 1.2) channels shape the cardiac action potential waveform and are essential for excitation\u2013contraction coupling in heart. A gain-of-function G406R mutation in a cytoplasmic loop of Ca\n V<\/jats:sub>\n 1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances Ca\n V<\/jats:sub>\n 1.2-LQT8 currents and generates lethal arrhythmias are unclear.\n <\/jats:p>\n <\/jats:sec>\n \n \n Objective:<\/jats:underline>\n <\/jats:title>\n \n To test the hypothesis that the anchoring protein AKAP150 modulates Ca\n V<\/jats:sub>\n 1.2-LQT8 channel gating in ventricular myocytes.\n <\/jats:p>\n <\/jats:sec>\n \n \n Methods and Results:<\/jats:underline>\n <\/jats:title>\n \n Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that Ca\n V<\/jats:sub>\n 1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca\n V<\/jats:sub>\n 1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of Ca\n V<\/jats:sub>\n 1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in Ca\n V<\/jats:sub>\n 1.2-LQT8 channels and protects the heart from arrhythmias.\n <\/jats:p>\n <\/jats:sec>\n \n \n Conclusion:<\/jats:underline>\n <\/jats:title>\n \n We propose that AKAP150-dependent changes in Ca\n V<\/jats:sub>\n 1.2-LQT8 channel gating may constitute a novel general mechanism for Ca\n V<\/jats:sub>\n 1.2-driven arrhythmias.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.111.248252","type":"journal-article","created":{"date-parts":[[2011,6,24]],"date-time":"2011-06-24T00:19:34Z","timestamp":1308874774000},"page":"255-261","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":96,"title":["Restoration of Normal L-Type Ca\n 2+<\/sup>\n Channel Function During Timothy Syndrome by Ablation of an Anchoring Protein"],"prefix":"10.1161","volume":"109","author":[{"given":"Edward P.","family":"Cheng","sequence":"first","affiliation":[{"name":"From the Department of Physiology & Biophysics, University of Washington, Seattle, WA (E.P.C., C.Y., M.F.N., R.E.D., M.N.-C., L.F.S.), and the Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA (J.D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Yuan","sequence":"additional","affiliation":[{"name":"From the Department of Physiology & Biophysics, University of Washington, Seattle, WA (E.P.C., C.Y., M.F.N., R.E.D., M.N.-C., L.F.S.), and the Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA (J.D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel F.","family":"Navedo","sequence":"additional","affiliation":[{"name":"From the Department of Physiology & Biophysics, University of Washington, Seattle, WA (E.P.C., C.Y., M.F.N., R.E.D., M.N.-C., L.F.S.), and the Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA (J.D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose E.","family":"Dixon","sequence":"additional","affiliation":[{"name":"From the Department of Physiology & Biophysics, University of Washington, Seattle, WA (E.P.C., C.Y., M.F.N., R.E.D., M.N.-C., L.F.S.), and the Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA (J.D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Nieves-Cintr\u00f3n","sequence":"additional","affiliation":[{"name":"From the Department of Physiology & Biophysics, University of Washington, Seattle, WA (E.P.C., C.Y., M.F.N., R.E.D., M.N.-C., L.F.S.), and the Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA (J.D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Scott","sequence":"additional","affiliation":[{"name":"From the Department of Physiology & Biophysics, University of Washington, Seattle, WA (E.P.C., C.Y., M.F.N., R.E.D., M.N.-C., L.F.S.), and the Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA (J.D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis F.","family":"Santana","sequence":"additional","affiliation":[{"name":"From the Department of Physiology & Biophysics, University of Washington, Seattle, WA (E.P.C., C.Y., M.F.N., R.E.D., M.N.-C., L.F.S.), and the Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA (J.D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.68.6.1501"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.09.011"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0710501105"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.108.788067"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.109.213363"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511322103"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.161737"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.109.216127"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7528941"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.06.032"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805922105"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0025-5564(95)00084-4"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.274.3.H747"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014400108"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.111.248252","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:43:59Z","timestamp":1715557439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.111.248252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,7,22]]},"references-count":14,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2011,7,22]]}},"alternative-id":["10.1161\/CIRCRESAHA.111.248252"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.111.248252","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.12480956.13697054","asserted-by":"object"}]},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,7,22]]},"assertion":[{"value":"2011-05-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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