{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:47:10Z","timestamp":1791352030990,"version":"4.3.1"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2013,11,18]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The small\n              <jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>\n              ase Rad is a negative regulator of voltage\u2010dependent L\u2010type calcium channel current (\n              <jats:styled-content style=\"fixed-case\">\n                I\n                <jats:sub>C<\/jats:sub>\n              <\/jats:styled-content>\n              <jats:sub>aL<\/jats:sub>\n              ); however, the effects of Rad ablation on cardiomyocyte function are unknown. The objective of this study is to test the hypothesis that Rad\u2010depletion causes positive inotropic effects without inducing cardiac hypertrophy.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Ventricular myocytes from adult Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice were isolated and evaluated by patch\u2010clamp recordings for I\n              <jats:sub>Ca,L<\/jats:sub>\n              and action potentials, Ca\n              <jats:sup>2+<\/jats:sup>\n              transients, and sarcomere shortening. Maximum I\n              <jats:sub>CaL<\/jats:sub>\n              is elevated in Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              (maximal conductance 0.35\u00b10.04\u00a0picoSiemens\/picoFarad (\n              <jats:styled-content style=\"fixed-case\">pS<\/jats:styled-content>\n              \/\n              <jats:styled-content style=\"fixed-case\">pF<\/jats:styled-content>\n              ) wild\u2010type; 0.61\u00b10.14\u00a0\n              <jats:styled-content style=\"fixed-case\">pS<\/jats:styled-content>\n              \/\n              <jats:styled-content style=\"fixed-case\">pF<\/jats:styled-content>\n              Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              ), decay kinetics are faster, and I\n              <jats:sub>Ca,L<\/jats:sub>\n              activates at lower voltages (activation midpoint \u22127.2\u00b10.6 wild\u2010type; \u221211.7\u00b10.9 Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              ) mimicking effects of \u03b2\u2010adrenergic receptor stimulation. Diastolic and twitch calcium are elevated in Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              (\n              <jats:italic>F<\/jats:italic>\n              <jats:sub>340\/380<\/jats:sub>\n              : 1.03 diastolic and 0.35 twitch for wild\u2010type; 1.47 diastolic and 0.736 twitch for Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              ) and sarcomere shortening is enhanced (4.31% wild\u2010type; 14.13% Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              ) at lower pacing frequencies. Consequentially, frequency\u2010dependence of Ca\n              <jats:sup>2+<\/jats:sup>\n              transients is less in Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              , and the frequency dependence of relaxation is also blunted. In isolated working hearts, similar results were obtained; chiefly, +\n              <jats:styled-content style=\"fixed-case\">dP<\/jats:styled-content>\n              \/dt was elevated at baseline and developed pressure was relatively nonresponsive to acute \u03b2\u2010adrenergic receptor stimulation. In single cells, at subphysiological frequencies, nonstimulated calmodulin\u2010dependent protein kinase\u2013sensitive calcium release is observed. Remarkably, Rad\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              hearts did not show hypertrophic growth despite elevated levels of diastolic calcium.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              This study demonstrates that the depletion of Rad\n              <jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>\n              ase is equivalent to sympathomimetic \u03b2\u2010adrenergic receptor, without stimulating cardiac hypertrophy. Thus, targeting Rad\n              <jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>\n              ase is a novel potential therapeutic target for Ca\n              <jats:sup>2+<\/jats:sup>\n              \u2010homeostasis\u2013driven positive inotropic support of the heart.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.113.000459","type":"journal-article","created":{"date-parts":[[2013,12,13]],"date-time":"2013-12-13T04:06:51Z","timestamp":1386907611000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":58,"title":["Rad GTPase Deletion Increases L\u2010type Calcium Channel Current Leading to Increased Cardiac Contraction"],"prefix":"10.1161","volume":"2","author":[{"given":"Janet R.","family":"Manning","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Kentucky College of Medicine, Lexington, KY"},{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine N.","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janos","family":"Magyar","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Kentucky College of Medicine, Lexington, KY"},{"name":"Department of Physiology, University of Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han\u2010Zhong","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Physiology, Wayne State University School of Medicine, Detroit, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Penn","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"Sievert","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.\u2010P.","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Physiology, Wayne State University School of Medicine, Detroit, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas A.","family":"Andres","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Satin","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Kentucky College of Medicine, Lexington, 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