{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:11:35Z","timestamp":1791209495531,"version":"4.1.0"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"5","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,3,4]]},"abstract":"<jats:p>\n                    Heterotrimeric G proteins, composed of G\u03b1 and G\u03b2\u03b3 subunits, transmit signals from cell surface receptors to cellular effector enzymes and ion channels. The G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    protein is the most abundant G\u03b1 subtype in the nervous system, but it is also found in the heart. Its function is not completely known, although it is required for regulation of N-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channels in GH\n                    <jats:sub>3<\/jats:sub>\n                    cells and also interacts with GAP43, a major protein in growth cones, suggesting a role in neuronal pathfinding. To analyze the function of G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    , we have generated mice lacking both isoforms of G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    by homologous recombination. Surprisingly, the nervous system is grossly intact, despite the fact that G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    makes up 0.2\u20130.5% of brain particulate protein and 10% of the growth cone membrane. The G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    \u2212\/\u2212 mice do suffer tremors and occasional seizures, but there is no obvious histologic abnormality in the nervous system. In contrast, G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    \u2212\/\u2212 mice have a clear and specific defect in ion channel regulation in the heart. Normal muscarinic regulation of L-type calcium channels in ventricular myocytes is absent in the mutant mice. The L-type calcium channel responds normally to isoproterenol, but there is no evident muscarinic inhibition. Muscarinic regulation of atrial K\n                    <jats:sup>+<\/jats:sup>\n                    channels is normal, as is the electrocardiogram. The levels of other G\u03b1 subunits (G\u03b1\n                    <jats:sub>s<\/jats:sub>\n                    , G\u03b1\n                    <jats:sub>q<\/jats:sub>\n                    , and G\u03b1\n                    <jats:sub>i<\/jats:sub>\n                    ) are unchanged in the hearts of G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    \u2212\/\u2212 mice, but the amount of G\u03b2\u03b3 is decreased. Whichever subunit, G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    or G\u03b2\u03b3, carries the signal forward, these studies show that muscarinic inhibition of L-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channels requires coupling of the muscarinic receptor to G\u03b1\n                    <jats:sub>o<\/jats:sub>\n                    . Other cardiac G\u03b1 subunits cannot substitute.\n                  <\/jats:p>","DOI":"10.1073\/pnas.94.5.1727","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:31:39Z","timestamp":1027679499000},"page":"1727-1732","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":117,"title":["G\u03b1\n                    <sub>o<\/sub>\n                    is necessary for muscarinic regulation of Ca\n                    <sup>2+<\/sup>\n                    channels in\u2009mouse\u2009heart"],"prefix":"10.1073","volume":"94","author":[{"given":"D.","family":"Valenzuela","sequence":"first","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Han","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U.","family":"Mende","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Fankhauser","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Mashimo","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Huang","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Pfeffer","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. J.","family":"Neer","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. C.","family":"Fishman","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Biology and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Department of Medicine, Cardiovascular Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1997,3,4]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)89881-7"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)89817-9"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)85162-1"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1988.tb10588.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/344836a0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490380208"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.1.1.125"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)51501-5"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)51502-7"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)51503-9"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0898-6568(91)90063-Z"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1990.tb08261.x"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7886455"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7886454"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/353043a0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/325445a0"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.10.3633"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(88)90206-1"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3144040"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(89)90030-5"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)38921-4"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)84578-7"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.9.4062"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)35732-0"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3181071"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00437a035"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.5.9.1513"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/227680a0"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)54955-3"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90495-6"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00656997"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.2.253"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8418498"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.8.3209"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/325321a0"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.49.29059"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1995.75.4.865"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1994.74.2.365"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90407-7"},{"key":"e_1_3_2_41_2","unstructured":"Bers D.\u2009M. 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