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'Discovery': [132], 'Institute,': [133], 'Center,': [138], 'OH': [139, 1465], '(J.S.S.).': [140], 'Originally': [141, 2418], 'published25': [142], 'May': [143, 2402], '2018https://doi.org/10.1161/CIRCRESAHA.118.313109Circulation': [144], 'Research.': [145], '2018;122:1485–1487GSK3': [146], '(glycogen': [147, 443], 'synthase': [148, 444, 1495], 'kinase-3)—one': [149], 'busiest': [152], 'kinases': [153, 392, 531, 552, 667], 'in': [154, 221, 260, 314, 391, 546, 563, 581, 623, 652, 710, 718, 791, 898, 905, 910, 916, 925, 935, 944, 953, 1000, 1012, 1030, 1075, 1244, 1275, 1285, 1289, 1405, 1424, 1614, 1642, 1913, 2090, 2206, 2234, 2274, 2285, 2317, 2338, 2367], 'cells—phosphorylates': [155], '>100': [156], 'known': [157, 878, 1350], 'substrates.': [158, 236, 253, 763], 'Typical': [159], 'substrates': [160, 186, 534, 672, 725, 767, 1404], 'GSK3': [162, 185, 1008], 'contain': [163, 770], 'a': [164, 178, 298, 352, 419, 646, 669, 702, 821, 839, 940, 1069, 1097, 1101, 1142, 1188, 1230, 1317, 1320, 1391, 1734], 'phosphorylated': [165, 179, 896], 'priming': [166, 778, 800], 'sequence,': [167], 'S/T-X-X-X-S/T(P),': [168], 'where': [169, 759], 'GSK3-targeted': [171], 'serine/threonine': [172], 'lies': [173], '4': [174], 'residues': [175, 313], 'N-terminal': [176, 514, 574, 1760], 'serine/threonine.': [180], 'The': [181, 678], 'large': [182], 'number': [183], 'their': [188, 396, 533, 880, 1136], 'location': [189], 'within': [190, 356, 844, 1301], 'different': [191, 1027], 'cellular': [192, 858, 1002, 1033, 1094, 1821], 'compartments': [193], 'raise': [194], 'question': [196, 1080], 'how': [198, 683], 'selectivity': [199], 'specificity': [201, 687], 'GSK3/substrate': [203], 'interactions': [204, 529], 'are': [205, 377, 415, 809, 870, 876, 984, 1004, 1018, 1427], 'achieved.': [206], 'In': [207, 1182], 'this': [208, 255, 865, 1150, 1226, 1425], 'issue,': [209], 'Wang': [210, 237, 745, 1470, 1810, 1812, 2034], 'et': [211, 238, 746, 1329], 'al1': [212, 747, 1330], 'demonstrate': [213], 'that': [214, 225, 248, 749, 793, 875, 1233, 1333, 1351, 1386], 'S-nitrosylation': [215, 245, 277, 350, 371, 382, 423, 429, 435, 440, 455, 468, 549, 580, 589, 644, 684, 750, 814, 853, 947, 1039, 1084, 1107, 1139, 1269, 1334, 1397, 1492, 1544, 1587, 1608, 1791, 1875, 1936, 2089, 2146], 'GSK3β': [217, 227, 250, 442, 696, 706, 739, 752, 754, 769, 792, 816, 1017, 1035, 1090, 1336], 'inhibits': [218, 363, 431, 594, 625], 'its': [219, 600, 956, 1161, 1338, 1501], 'activity': [220, 288, 1163, 1214, 1695], 'cytosol': [223], 'S-nitrosylated': [226, 1294], '(SNO-GSK3β)': [228], 'translocates': [229], 'nucleus': [232, 758, 1342], 'phosphorylate': [234], 'nuclear': [235, 724, 740, 762, 766, 827, 1192, 1353, 1392, 1852], 'al': [239], 'thus': [240, 1141, 1314], 'uncover': [241], 'novel': [242], 'interplay': [243, 256], 'between': [244, 276, 530, 639, 996, 1127], 'phosphorylation': [247, 279, 303, 425, 538, 627, 855, 965, 999, 1264, 1281, 1502], 'subserves': [249], 'targeting': [251], 'Interestingly,': [254, 764, 933, 1257], 'may': [257, 783, 1388], 'be': [258, 701, 784, 894, 1260, 1379], 'relevant': [259], 'heart': [261], 'failure.Article,': [262], 'see': [263], 'p': [264], '1517S-Nitrosylation': [265], 'Directly': [266], 'Suppresses': [267], 'Activity': [268], 'Protein': [270, 835, 1098, 1102, 1491, 2006, 2199], 'KinasesIn': [271], 'many': [272, 378, 541, 765], 'cases,': [273], 'cross': [274, 426, 994], 'talk': [275, 995], 'is': [280, 297, 347, 561, 697, 707, 742, 927, 937, 1036, 1054, 1072, 1140, 1152, 1221, 1229, 1242, 1293, 1313, 1348, 2271], 'manifested': [281], 'by': [282, 349, 394, 635, 688, 852, 939, 948, 974, 1038, 1154, 1262, 1381, 1412, 1543, 1730, 1764, 1946, 2049, 2145, 2391], 'S-nitrosylation–mediated': [283], 'suppression': [284], 'protein': [286, 412, 480, 492, 519, 551, 606, 613, 850, 1206, 1610, 1699, 1762, 1822], 'kinase': [287, 295, 345, 364, 400, 404, 413, 432, 472, 475, 481, 493, 507, 520, 607, 608, 614, 615, 676, 1219, 1232, 1310, 1318, 1496, 1548, 1611, 1640, 1675, 1700, 1728, 1763], '(Figure': [289, 694, 867, 1327], '[A]).': [290], 'GRK2': [291], '(G': [292, 887], 'protein-coupled': [293, 505, 888, 1584], 'receptor': [294, 330, 374, 506, 1541, 1547, 1585, 1796], '2)': [296], 'prime': [299], 'example.2': [300], 'Specifically,': [301], 'GRK2-mediated': [302], 'β-AR': [306], '(β-adrenergic': [307], 'receptor)': [308], 'at': [309, 592, 918, 1040, 1295, 1399], 'serine': [310], 'threonine': [312], "β-AR's": [315], 'arrestin-binding': [316], 'domain': [317], 'promotes': [318, 955, 1165, 1337], 'β-arrestin': [319], 'binding,': [320], 'which': [321, 362, 578, 1061, 1173, 1253, 1299], 'prevents': [322, 373, 2141], 'further': [323], 'activation': [324, 346, 358, 1248], 'G': [326, 504, 1583, 1977, 2084, 2165, 2194, 2329, 2341], 'proteins': [327, 874, 1146], 'initiates': [329], 'internalization': [331, 971], 'desensitization.': [333], 'β-ARs': [334], 'do': [335], 'not,': [336], 'however,': [337, 705], 'desensitize': [338, 885], 'under': [339], 'normal': [340], 'physiological': [341, 653], 'conditions': [342], 'because': [343, 785], 'receptor-mediated': [344], 'followed': [348], 'critical': [353], 'Cys': [354], '(Cys340)': [355], 'loop': [359], 'GRK2,': [361, 503], 'activity.2': [365], 'β-AR–coupled,': [366], 'endothelial': [367, 496, 949], 'NOS': [368, 950], '(NO': [369], 'synthase)–mediated': [370], 'thereby': [372, 960, 1208, 1308], 'inactivation.3': [375], 'There': [376], 'other': [379, 719], 'examples': [380], 'inhibiting': [383, 1309], 'phosphorylation-based': [384], 'signal': [385], 'transduction': [386], 'through': [387, 1247, 1676, 1733], 'induced': [388, 1945], 'conformational': [389, 789], 'changes': [390, 441], 'or': [393, 1434], 'blocking': [395], 'autophosphorylation:': [397], 'PKC': [398], '(protein': [399, 403], 'C),4': [401], 'AKT': [402, 478], 'B),5': [405], 'IKK': [406], '(IκB': [407], 'kinase),6': [408], 'CaMKII': [410], '(calcium/calmodulin-dependent': [411], 'II)7': [414], 'name': [417], 'but': [418, 1050, 1067], 'few.Download': [420], 'figureDownload': [421], 'PowerPointFigure.': [422], 'talk.': [427], 'A,': [428, 1515, 1667, 1809, 1870, 1891, 1972, 2077, 2221, 2303], 'directly': [430], 'activity.': [433, 1138], 'B,': [434, 1487, 2217], 'disrupts': [436], 'kinase–substrate': [437], 'interaction.': [438], 'C,': [439, 2379], 'kinase-3)': [445], 'localization': [446, 691, 741], 'determines': [448, 685, 1589], 'substrate': [449, 650, 663, 686], 'specificity.': [450], 'D,': [451, 1805], '(P)': [453], 'alternatively': [456], 'modify': [457, 1087], 'β-arr1': [458], '(β-arrestin1)': [459], 'β-arr2': [461], '(β-arrestin2)': [462], 'regulate': [464, 649], 'GPCR': [465], 'internalization.': [466, 932], 'E,': [467, 1558, 1627, 1893, 2122, 2132], 'converts': [469], 'CDK5': [470, 1228, 1241, 1292, 1906], '(cyclin-dependent': [471, 1218], '5)': [473, 1220], 'from': [474, 797, 1135, 1316], 'nitrosylase.': [477], 'indicates': [479], 'B;': [482], 'ASK,': [483], 'apoptosis': [484, 1726], 'signal-regulating': [485, 569, 1727], 'kinase;': [486, 502, 511, 515], 'β-AR,': [487], 'β-adrenergic': [488], 'receptor;': [489], 'CaMKII,': [490], 'calcium/calmodulin-dependent': [491], 'II;': [494], 'eNOS,': [495], 'NO': [497, 1125], 'synthase;': [498], 'ERK,': [499], 'extracellular': [500, 2099], 'signal-regulated': [501], '2;': [508], 'IKK,': [509], 'IκB': [510], 'JNK,': [512], 'Jun': [513], 'P,': [516, 1868, 2189], 'phosphorylation;': [517], 'PKC,': [518], 'C;': [521], 'SNO,': [523], 'S-nitrosothiol': [524], '(S-nitrosylation).S-Nitrosylation': [525], 'Affects': [526], 'Kinase-Substrate': [527], 'SpecificityProductive': [528], 'identify': [535], 'bona': [536], 'fide': [537], 'sites': [539, 545], '(among': [540], 'thousands': [542], 'candidate': [544], 'proteome).': [548], 'can': [553, 856, 893, 1085, 1259, 1377], 'influence': [554], 'these': [555, 987, 1403], 'kinase/substrate': [556], 'interactions.': [557], 'This': [558, 781, 1053, 1077], 'operating': [559, 1113], 'principle': [560, 866, 1151], 'illustrated': [562, 1153], 'cases': [565], 'ASK1': [567, 591, 598], '(apoptosis': [568], 'kinase-1)': [570], 'JNK': [572, 624, 640], '(Jun': [573], 'kinases;': [575], 'Figure': [576], '[B]),': [577], 'undergo': [579], 'response': [582, 1031, 2286], 'apoptotic': [584, 618], 'stimuli.8,9': [585], 'For': [586], 'example,': [587], 'interferon-γ–induced': [588], 'Cys869': [593], 'binding': [596, 957, 1166], 'principal': [601], 'downstream': [602], 'effectors': [603], 'MKK3': [604], '(mitogen-activated': [605, 612], '3)': [609], 'MKK6': [611], '6),': [616], 'attenuating': [617], 'cell': [619], 'death.8S-nitrosylation': [620], 'Cys116': [622], 'JNK-mediated': [626], 'transactivation': [629], 'c-Jun': [631, 1759], '(transcription': [632], 'factor': [633, 1360], 'AP-1)': [634], 'disrupting': [636], 'interaction': [638, 2095], 'c-Jun.9': [642], 'Thus,': [643, 964], 'provides': [645, 656], 'mechanism': [647, 660, 822, 841], 'recognition': [651, 796, 824], 'context.Subcellular': [654], 'compartmentalization': [655, 665], 'another': [657, 1222], 'commonly': [658], 'exploited': [659], 'achieve': [662], 'specificity;': [664], 'restricts': [666], 'subset': [670], 'increases': [674], 'local': [675], 'concentrations.': [677], 'present': [679, 1073], 'study': [680], 'illustrates': [681, 864], 'elegantly': [682], 'changing': [689], 'GSK3β1': [693], '[C]).': [695], 'traditionally': [698], 'considered': [699], 'cytosolic': [703], 'protein;': [704], 'also': [708, 1378], 'found': [709, 748], 'mitochondria': [712], 'nucleus,': [714, 1184], 'as': [715, 717, 980, 1081, 1187, 1390, 2347], 'well': [716, 1349], 'subcellular': [720], 'compartments.': [721], 'Although': [722, 1014], 'numerous': [723, 1023, 1191], 'GSK3β,': [727, 1356], 'including': [728, 1194, 1357], 'transcriptional': [729, 1211], 'factors': [730], 'epigenetic': [732], 'regulators,': [733], 'have': [734, 1131], 'been': [735], 'identified,': [736], 'regulation': [737, 1981], 'poorly': [743], 'understood.': [744], 'causes': [753], 'translocation': [755, 1176], 'it': [760, 1347], 'phosphorylates': [761, 1234, 1907], 'an': [771, 787, 803, 1296], 'S/T-P': [772, 828], 'motif': [773], 'rather': [774], 'than': [775], 'prototypical': [777], 'sequence': [779], 'S/T-X-X-X-S/T(P).': [780], 'nuance': [782], 'S-nitrosylation–induced': [788], 'change': [790], 'shifts': [794], 'structure-based': [795], 'canonical': [799, 1132], 'site': [801, 1065], 'alternate': [804], 'phospho-targeting': [805], 'motif.': [806], 'More': [807], 'studies': [808], 'needed': [810], 'determine': [812], 'whether': [813, 1083], 'has': [817], 'evolved': [818], 'provide': [820, 838], 'motif.S-Nitrosylation': [829], 'Selectively': [832], 'Modify': [833], 'Different': [834], 'IsoformsProtein': [836], 'isoforms': [837, 851, 1006], 'natural': [840], 'divergence': [843], 'signaling': [845, 1542, 1588], 'networks.': [846], 'Differential': [847], 'modification': [848, 861], 'versus': [854], 'fine-tune': [857], 'signaling.': [859], 'Post-translational': [860], 'β-arrestins': [863, 869], '[D]).': [868], 'versatile,': [871], 'multifunctional': [872], 'scaffold': [873], 'best': [877], 'ability': [881], 'internalize': [883], 'GPCRs': [886, 973], 'receptors).': [889], 'β-arrestin1': [890, 899, 911, 926, 936, 975, 981, 1058], 'β-arrestin2': [892, 954, 983], 'both': [895, 1263], '(Ser412': [897], 'Thr276,': [901], 'Ser361,': [902], 'Thr383': [904], 'β-arrestin2)': [906, 917], 'nitrosylated': [908], '(Cys251': [909], 'Cys253': [913], 'Cys410': [915, 943, 952], 'multiple': [919, 1352], 'loci.': [920], 'Stimulus-coupled': [921], 'dephosphorylation': [922], 'Ser412': [924, 934], 'requisite': [928], 'clathrin-mediated': [930, 970], 'β2-AR': [931, 962], 'replaced': [938], 'highly': [941], 'conserved': [942], 'β-arrestin2,': [945, 977, 1060], 'clathrin,': [959], 'accelerating': [961], 'internalization.10': [963], 'nitrosylation': [967, 997, 1850, 2169], 'subserve': [968], 'classic': [969], 'respectively.': [978], 'Inasmuch': [979], 'ubiquitously': [985, 1019], 'distributed,': [986], 'data': [988], 'support': [989], 'idea': [991], 'functional': [993], 'wide-ranging': [1001], 'functions.There': [1003], '2': [1005], '(GSK3α': [1009], 'GSK3β)': [1011], 'mammals.': [1013], 'GSK3α': [1015, 1045, 1088], 'expressed': [1020, 1423], 'share': [1022, 1062], 'substrates,': [1024], 'they': [1025], 'mediate': [1026, 1092, 1121, 1395], 'biological': [1028], 'functions': [1029, 1133], 'stimuli.': [1034], 'modified': [1037, 1380], 'Cys76,': [1041], 'Cys199,': [1042], 'Cys317;': [1044], 'contains': [1046], 'Cys199': [1047], 'Cys317': [1049], 'lacks': [1051], 'Cys76.1': [1052], 'somewhat': [1055], 'akin': [1056], '1': [1063, 1729], 'SNO': [1064, 1116], '(Cys251/253)': [1066], 'not': [1068, 1428], 'second': [1070], '(C410': [1071], 'only': [1074], 'β-arrestin2).': [1076], 'raises': [1078], 'selectively': [1086], 'distinct': [1093], 'functions.S-Nitrosylation': [1095], 'Converts': [1096], 'Kinase': [1099], 'Into': [1100], 'NitrosylaseThe': [1103], 'machinery': [1104, 1819], 'enzymatic': [1106, 1818], 'involves': [1108], '3': [1109], 'classes': [1110], 'enzymes': [1112], 'coordinately:': [1114], 'NOS,': [1115], 'synthases,': [1117], 'transnitrosylases.11': [1119], 'Transnitrosylases': [1120], 'thiol-based': [1122], 'transfer': [1123], 'groups': [1126], 'proteins.': [1128], 'Most': [1129], 'transnitrosylases': [1130], 'apart': [1134], 'transnitrosylase': [1137, 1189, 1393], 'prerequisite': [1143], 'convert': [1145], 'into': [1147, 1319, 1340], 'nascent': [1148], 'nitrosylases;': [1149], 'GAPDH—a': [1155], 'prototypic': [1156], 'transnitrosylase.12S-nitrosylation': [1157], 'GAPDH': [1159, 1848], 'abolishes': [1160], 'catalytic': [1162], 'E3': [1169], 'ubiquitin': [1170], 'ligase': [1171], 'Siah,': [1172], 'subsequently': [1174], 'facilitates': [1175], 'SNO-GAPDH': [1178, 1185], 'nucleus.': [1181], 'acts': [1186], 'proteins,': [1193], 'deacetylating': [1196], 'enzyme': [1197], 'SIRT1': [1198], '(sirtuin-1),': [1199], 'HDAC2': [1200], '(histone': [1201], 'deacetylase-2),': [1202], 'DNA-PK': [1204], '(DNA-activated': [1205], 'kinase),12': [1207], 'regulating': [1209], 'metabolic': [1213], 'cell.CDK5': [1217], 'elegant': [1223], 'example': [1224], 'principle.': [1227], 'proline-directed': [1231], 'serines/threonines': [1235], 'immediately': [1236], 'upstream': [1237], 'proline': [1239], 'residues.': [1240], 'implicated': [1243], 'neuronal': [1245, 1883, 1915], 'injury': [1246], 'Drp1': [1250, 1258, 1321, 1877], '(dynamin-1-like': [1251], 'protein),': [1252], 'induces': [1254, 1693], 'mitochondrial': [1255, 1273, 1283, 1880, 1911], 'fission.': [1256], 'activated': [1261, 1363], 'S-nitrosylation.': [1266, 1382], 'But': [1267], 'whereas': [1268], 'Drp1-Cys644': [1271], 'mediates': [1272, 1282, 1849, 1878], 'fission': [1274, 1284, 1881], 'Alzheimer': [1276, 1290], '(and': [1277], 'Huntington)': [1278], 'models,13': [1279], 'Ser585': [1280], 'NMDA-induced': [1286, 1914], 'injury.14': [1287], 'Notably,': [1288], 'disease,': [1291], 'essential': [1297], 'Cys83,': [1298], 'resides': [1300], 'ATP-binding': [1303], 'pocket': [1304], 'kinase,': [1307], 'activity;': [1311], 'SNO-CDK5': [1312], 'converted': [1315], 'transnitrosylase,': [1322], 'possibly': [1323], 'mediating': [1324], 'synaptic': [1325, 1942], 'damage15': [1326], '[E]).Wang': [1328], 'show': [1331], 'here': [1332], 'trafficking': [1339], 'myocardial': [1344], 'cells,': [1345], 'phospho-substrates': [1354], 'NF-κB': [1358], '(nuclear': [1359], 'kappa-light-chain-enhancer': [1361], 'B': [1364, 1641, 2134], 'cells),': [1365], 'p53,': [1366], 'STAT3': [1367], '(signal': [1368], 'transducer': [1369], 'activator': [1371], 'transcription': [1373], '3),': [1374], 'Sirt1,': [1376], 'It': [1383], 'seems': [1384], 'likely': [1385], 'SNO-GSK3β': [1387], 'act': [1389], 'least': [1400], 'some': [1401], 'myocardium.Sources': [1406], 'FundingThis': [1408], 'work': [1409], 'was': [1410], 'supported': [1411], 'National': [1413], 'Institutes': [1414], 'Health': [1416], 'grants': [1417], 'HL075443,': [1418], 'HL128192,': [1419], 'HL126900.DisclosuresNone.FootnotesThe': [1421], 'opinions': [1422], 'article': [1426], 'necessarily': [1429], 'those': [1430], 'editors': [1433], 'American': [1437, 2413], 'Heart': [1438, 2414], 'Association.Correspondence': [1439], 'Stamler,': [1443], 'MD,': [1444, 1831], 'Wolstein': [1457], 'Research': [1458], 'Bldg': [1459], '4129,': [1460], '2103': [1461], 'Cornell': [1462], 'Rd,': [1463], 'Cleveland,': [1464], '44106.': [1466], 'E-mail': [1467], '[email': [1468], 'protected]References1.': [1469], 'S-B,': [1471], 'Venkatraman': [1472], 'V,': [1473, 1968], 'Crowgey': [1474], 'EL,': [1475], 'Liu': [1476], 'T,': [1477, 1625, 1864, 1927, 1970], 'Fu': [1478], 'Z,': [1479, 1872, 1999], 'Holewinski': [1480], 'R,': [1481, 2075], 'Ranek': [1482], 'M,': [1483, 1525, 1574, 2073, 2116, 2120, 2124, 2262], 'Kass': [1484], 'DA,': [1485], "O'Rourke": [1486], 'Van': [1488], 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