Department of Pharmacology

Research Description

Ion channels are critical for normal electrical activity in cardiac and vascular smooth muscle, while even mild dysfunction can cause life-threatening cardiac arrhythmias in humans. The principal goal of our research is to investigate the signaling processes and proteins that modulate the activity of cardiovascular ion channels. Circulating hormones that activate intracellular signaling cascades, and ultimately protein kinases, can rapidly regulate ion channel function. Our recent work demonstrates that protein kinases can also modify intracellular trafficking of cardiac sodium channels to alter expression at the cell surface. Given the critical role of these channels in electrical impulse conduction, we are actively investigating the molecular features of this process. We have also chosen to study a potassium channel signaling complex that underlies an important repolarizing current, IKur. Because IKur is atrial-specific in humans, it represents an attractive target for pharmacologic therapy of cardiac arrhythmias, and improved understanding of its molecular components would permit optimal drug design. Another area of interest is the electrical remodeling that occurs with atrial fibrillation, a common cardiac arrhythmia that is a major cause of stroke and death in the US. The remodeling process causes the arrhythmia to perpetuate itself, rendering it refractory to treatment. An in vitro model of atrial fibrillation has been created to investigate basic mechanisms of development and associated changes in gene expression. These studies should improve our understanding of the molecular basis of ionic currents in the cardiovascular system and contribute to the development of new therapeutic approaches in treating cardiac arrhythmias.

• Ray WA, Chung CP, Murray KT, Hall K, Stein CM. High-Dose Citalopram and Escitalopram and the Risk of Out-of-Hospital Death. J Clin Psychiatry [print-electronic]. 2016 Oct 10/11/2016; PMID: 27736049, DOI: 10.4088/JCP.15m10324, ISSN: 1555-2101.
• Ray WA, Chung CP, Murray KT, Smalley WE, Daugherty JR, Dupont WD, Stein CM. Association of Proton Pump Inhibitors with Reduced Risk of Warfarin-related Serious Upper Gastrointestinal Bleeding. Gastroenterology [print-electronic]. 2016 Sep 9/14/2016; PMID: 27639805, PII: S0016-5085(16)35034-X, DOI: 10.1053/j.gastro.2016.08.054, ISSN: 1528-0012.
• Quintana MT, Parry TL, He J, Yates CC, Sidorova TN, Murray KT, Bain JR, Newgard CB, Muehlbauer MJ, Eaton SC, Hishiya A, Takayama S, Willis MS. Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling. Am. J. Pathol [print-electronic]. 2016 Aug; 186(8): 1989-2007. PMID: 27321750, PMCID: PMC4973657, PII: S0002-9440(16)30123-7, DOI: 10.1016/j.ajpath.2016.03.017, ISSN: 1525-2191.
• Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain. JAMA. 2016 Jun 6/14/2016; 315(22): 2415-23. PMID: 27299617, PMCID: PMC5030814, PII: 2528212, DOI: 10.1001/jama.2016.7789, ISSN: 1538-3598.
• Bultman SJ, Holley DW, G de Ridder G, Pizzo SV, Sidorova TN, Murray KT, Jensen BC, Wang Z, Bevilacqua A, Chen X, Quintana MT, Tannu M, Rosson GB, Pandya K, Willis MS. BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo. Cardiovasc. Pathol [print-electronic]. 2016 May; 25(3): 258-69. PMID: 27039070, PMCID: PMC4860071, PII: S1054-8807(16)30007-2, DOI: 10.1016/j.carpath.2016.02.004, ISSN: 1879-1336.
• Chung CP, Callahan ST, Cooper WO, Murray KT, Hall K, Dudley JA, Stein CM, Ray WA. Development of an algorithm to identify serious opioid toxicity in children. BMC Res Notes. 2015 Jul 7/4/2015; 8: 293. PMID: 26141980, PMCID: PMC4491206, PII: 10.1186/s13104-015-1185-x, DOI: 10.1186/s13104-015-1185-x, ISSN: 1756-0500.
• Ray WA, Chung CP, Murray KT, Cooper WO, Hall K, Stein CM. Out-of-hospital mortality among patients receiving methadone for noncancer pain. JAMA Intern Med. 2015 Mar; 175(3): 420-7. PMID: 25599329, PMCID: PMC4346542, PII: 2091400, DOI: 10.1001/jamainternmed.2014.6294, ISSN: 2168-6114.
• Kolek MJ, Muehlschlegel JD, Bush WS, Parvez B, Murray KT, Stein CM, Shoemaker MB, Blair MA, Kor KC, Roden DM, Donahue BS, Fox AA, Shernan SK, Collard CD, Body SC, Darbar D. Genetic and clinical risk prediction model for postoperative atrial fibrillation. Circ Arrhythm Electrophysiol [print-electronic]. 2015 Feb; 8(1): 25-31. PMID: 25567478, PMCID: PMC4334678, PII: CIRCEP.114.002300, DOI: 10.1161/CIRCEP.114.002300, ISSN: 1941-3084.
• Sidorova TN, Yermalitskaya LV, Mace LC, Wells KS, Boutaud O, Prinsen JK, Davies SS, Roberts LJ, Dikalov SI, Glabe CG, Amarnath V, Barnett JV, Murray KT. Reactive ¿-ketoaldehydes promote protein misfolding and preamyloid oligomer formation in rapidly-activated atrial cells. J. Mol. Cell. Cardiol [print-electronic]. 2015 Feb; 79: 295-302. PMID: 25463275, PMCID: PMC4302000, PII: S0022-2828(14)00373-3, DOI: 10.1016/j.yjmcc.2014.11.013, ISSN: 1095-8584.
• Darghosian L, Free M, Li J, Gebretsadik T, Bian A, Shintani A, McBride BF, Solus J, Milne G, Crossley GH, Thompson D, Vidaillet H, Okafor H, Darbar D, Murray KT, Stein CM. Effect of omega-three polyunsaturated fatty acids on inflammation, oxidative stress, and recurrence of atrial fibrillation. Am. J. Cardiol [print-electronic]. 2015 Jan 1/15/2015; 115(2): 196-201. PMID: 25465932, PMCID: PMC4276435, PII: S0002-9149(14)02010-4, DOI: 10.1016/j.amjcard.2014.10.022, ISSN: 1879-1913.
• Sidorova TN, Mace LC, Wells KS, Yermalitskaya LV, Su PF, Shyr Y, Atkinson JB, Fogo AB, Prinsen JK, Byrne JG, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Glabe CG, Brown NJ, Barnett JV, Murray KT. Hypertension is associated with preamyloid oligomers in human atrium: a missing link in atrial pathophysiology?. J Am Heart Assoc. 2014 Dec 12/2/2014; 3(6): e001384. PMID: 25468655, PMCID: PMC4338732, PII: jah3772, DOI: 10.1161/JAHA.114.001384, ISSN: 2047-9980.
• Sidorova TN, Mace LC, Wells KS, Yermalitskaya LV, Su PF, Shyr Y, Byrne JG, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Glabe CG, Brown NJ, Barnett JV, Murray KT. Quantitative Imaging of Preamyloid Oligomers, a Novel Structural Abnormality, in Human Atrial Samples. J. Histochem. Cytochem [print-electronic]. 2014 Jul; 62(7): 479-87. PMID: 24789805, PMCID: PMC4072180, PII: 0022155414535782, DOI: 10.1369/0022155414535782, ISSN: 1551-5044.
• Murray KT. It’s a funny thing… [editorial]. J. Cardiovasc. Electrophysiol [print-electronic]. 2013 Dec; 24(12): 1401-2. PMID: 24033556, DOI: 10.1111/jce.12232, ISSN: 1540-8167.
• Ray WA, Murray KT, Kawai V, Graham DJ, Cooper WO, Hall K, Stein CM. Propoxyphene and the risk of out-of-hospital death. Pharmacoepidemiol Drug Saf [print-electronic]. 2013 Apr; 22(4): 403-12. PMID: 23408551, PMCID: PMC3694329, DOI: 10.1002/pds.3411, ISSN: 1099-1557.
• Pretorius M, Murray KT, Yu C, Byrne JG, Billings FT, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Mishra V, Body SC, Brown NJ. Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery. Crit. Care Med. 2012 Oct; 40(10): 2805-12. PMID: 22824930, PMCID: PMC3588582, DOI: 10.1097/CCM.0b013e31825b8be2, ISSN: 1530-0293.
• Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N. Engl. J. Med. 2012 May 5/17/2012; 366(20): 1881-90. PMID: 22591294, PMCID: PMC3374857, DOI: 10.1056/NEJMoa1003833, ISSN: 1533-4406.
• Hallaq H, Wang DW, Kunic JD, George AL, Wells KS, Murray KT. Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na+ channels. Am. J. Physiol. Heart Circ. Physiol [print-electronic]. 2012 Feb 2/1/2012; 302(3): H782-9. PMID: 22101522, PMCID: PMC3353784, PII: ajpheart.00817.2010, DOI: 10.1152/ajpheart.00817.2010, ISSN: 1522-1539.
• Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O’Duffy A, Connell FA, Ray WA. ADHD drugs and serious cardiovascular events in children and young adults. N. Engl. J. Med [print-electronic]. 2011 Nov 11/17/2011; 365(20): 1896-904. PMID: 22043968, PMCID: PMC4943074, DOI: 10.1056/NEJMoa1110212, ISSN: 1533-4406.
• Yang Z, Murray KT. Ionic mechanisms of pacemaker activity in spontaneously contracting atrial HL-1 cells. J. Cardiovasc. Pharmacol. 2011 Jan; 57(1): 28-36. PMID: 20881602, PMCID: PMC3023001, DOI: 10.1097/FJC.0b013e3181fda7c4, ISSN: 1533-4023.
• Chung CP, Murray KT, Stein CM, Hall K, Ray WA. A computer case definition for sudden cardiac death. Pharmacoepidemiol Drug Saf. 2010 Jun; 19(6): 563-72. PMID: 20029823, PMCID: PMC3181496, DOI: 10.1002/pds.1888, ISSN: 1099-1557.
• Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty JR, Kaltenbach LA, Stein CM. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann. Intern. Med. 2010 Mar 3/16/2010; 152(6): 337-45. PMID: 20231564, PMCID: PMC3176584, PII: 152/6/337, DOI: 10.7326/0003-4819-152-6-201003160-00003, ISSN: 1539-3704.
• Mace LC, Yermalitskaya LV, Yi Y, Yang Z, Morgan AM, Murray KT. Transcriptional remodeling of rapidly stimulated HL-1 atrial myocytes exhibits concordance with human atrial fibrillation. J. Mol. Cell. Cardiol [print-electronic]. 2009 Oct; 47(4): 485-92. PMID: 19615375, PMCID: PMC2754068, PII: S0022-2828(09)00280-6, DOI: 10.1016/j.yjmcc.2009.07.006, ISSN: 1095-8584.
• Ray WA, Varas-Lorenzo C, Chung CP, Castellsague J, Murray KT, Stein CM, Daugherty JR, Arbogast PG, García-Rodríguez LA. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes [print-electronic]. 2009 May; 2(3): 155-63. PMID: 20031832, PII: CIRCOUTCOMES.108.805689, DOI: 10.1161/CIRCOUTCOMES.108.805689, ISSN: 1941-7705.
• Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N. Engl. J. Med. 2009 Jan 1/15/2009; 360(3): 225-35. PMID: 19144938, PMCID: PMC2713724, PII: 360/3/225, DOI: 10.1056/NEJMoa0806994, ISSN: 1533-4406.
• Fleming GA, Murray KT, Yu C, Byrne JG, Greelish JP, Petracek MR, Hoff SJ, Ball SK, Brown NJ, Pretorius M. Milrinone use is associated with postoperative atrial fibrillation after cardiac surgery. Circulation [print-electronic]. 2008 Oct 10/14/2008; 118(16): 1619-25. PMID: 18824641, PMCID: PMC2770257, PII: CIRCULATIONAHA.108.790162, DOI: 10.1161/CIRCULATIONAHA.108.790162, ISSN: 1524-4539.
• Ellis CR, Murray KT. When an ICD is not the answer… hypothyroidism-induced cardiomyopathy and torsades de pointes. J. Cardiovasc. Electrophysiol [print-electronic]. 2008 Oct; 19(10): 1105-7. PMID: 18399973, PII: JCE1154, DOI: 10.1111/j.1540-8167.2008.01154.x, ISSN: 1540-8167.
• Hebert PR, Coffey CS, Byrne DW, Scott TA, Fagard RH, Rottman JN, Murray KT, Oates JA. Treatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death. J Am Soc Hypertens. 2008 Sep; 2(5): 355-65. PMID: 19727429, PMCID: PMC2633478, DOI: 10.1016/j.jash.2008.04.001, ISSN: 1933-1711.
• Yang Z, Browning CF, Hallaq H, Yermalitskaya L, Esker J, Hall MR, Link AJ, Ham AJ, McGrath MJ, Mitchell CA, Murray KT. Four and a half LIM protein 1: a partner for KCNA5 in human atrium. Cardiovasc. Res [print-electronic]. 2008 Jun 6/1/2008; 78(3): 449-57. PMID: 18281375, PII: cvn038, DOI: 10.1093/cvr/cvn038, ISSN: 0008-6363.
• Murray KT, Mace LC, Yang Z. Nonantiarrhythmic drug therapy for atrial fibrillation. Heart Rhythm [print-electronic]. 2007 Mar; 4(3 Suppl): S88-90. PMID: 17336893, PII: S1547-5271(06)02275-2, DOI: 10.1016/j.hrthm.2006.12.027, ISSN: 1547-5271.
• Hallaq H, Yang Z, Viswanathan PC, Fukuda K, Shen W, Wang DW, Wells KS, Zhou J, Yi J, Murray KT. Quantitation of protein kinase A-mediated trafficking of cardiac sodium channels in living cells. Cardiovasc. Res [print-electronic]. 2006 Nov 11/1/2006; 72(2): 250-61. PMID: 16973141, PII: S0008-6363(06)00382-8, DOI: 10.1016/j.cardiores.2006.08.007, ISSN: 0008-6363.
• Kannankeril PJ, Roden DM, Norris KJ, Whalen SP, George AL, Murray KT. Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives. Heart Rhythm. 2005 Feb; 2(2): 134-40. PMID: 15851285, PII: S1547-5271(04)00777-5, DOI: 10.1016/j.hrthm.2004.10.039, ISSN: 1547-5271.
• Lundquist AL, Manderfield LJ, Vanoye CG, Rogers CS, Donahue BS, Chang PA, Drinkwater DC, Murray KT, George AL. Expression of multiple KCNE genes in human heart may enable variable modulation of I(Ks). J. Mol. Cell. Cardiol [print-electronic]. 2005 Feb; 38(2): 277-87. PMID: 15698834, PII: S0022-2828(04)00333-5, DOI: 10.1016/j.yjmcc.2004.11.012, ISSN: 0022-2828.
• Yang Z, Shen W, Rottman JN, Wikswo JP, Murray KT. Rapid stimulation causes electrical remodeling in cultured atrial myocytes. J. Mol. Cell. Cardiol [print-electronic]. 2005 Feb; 38(2): 299-308. PMID: 15698836, PII: S0022-2828(04)00336-0, DOI: 10.1016/j.yjmcc.2004.11.015, ISSN: 0022-2828.
• Murray KT, Rottman JN, Arbogast PG, Shemanski L, Primm RK, Campbell WB, Solomon AJ, Olgin JE, Wilson MJ, Dimarco JP, Beckman KJ, Dennish G, Naccarelli GV, Ray WA, . Inhibition of angiotensin II signaling and recurrence of atrial fibrillation in AFFIRM. Heart Rhythm. 2004 Dec; 1(6): 669-75. PMID: 15851238, PII: S1547-5271(04)00419-9, DOI: 10.1016/j.hrthm.2004.08.008, ISSN: 1547-5271.
• Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin and the risk of sudden death from cardiac causes. N. Engl. J. Med. 2004 Sep 9/9/2004; 351(11): 1089-96. PMID: 15356306, PII: 351/11/1089, DOI: 10.1056/NEJMoa040582, ISSN: 1533-4406.
• Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin. Pharmacol. Ther. 2004 Mar; 75(3): 234-41. PMID: 15001975, PII: S000992360300331X, DOI: 10.1016/j.clpt.2003.09.019, ISSN: 0009-9236.
• Zhou J, Shin HG, Yi J, Shen W, Williams CP, Murray KT. Phosphorylation and putative ER retention signals are required for protein kinase A-mediated potentiation of cardiac sodium current. Circ. Res. 2002 Sep 9/20/2002; 91(6): 540-6. PMID: 12242273, ISSN: 1524-4571.
• Williams CP, Hu N, Shen W, Mashburn AB, Murray KT. Modulation of the human Kv1.5 channel by protein kinase C activation: role of the Kvbeta1.2 subunit. J. Pharmacol. Exp. Ther. 2002 Aug; 302(2): 545-50. PMID: 12130714, DOI: 10.1124/jpet.102.033357, ISSN: 0022-3565.
• Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL, Roden DM. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation. 2002 Apr 4/23/2002; 105(16): 1943-8. PMID: 11997281, ISSN: 1524-4539.
• Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch. Gen. Psychiatry. 2001 Dec; 58(12): 1161-7. PMID: 11735845, PII: yoa20305, ISSN: 0003-990X.
• Shin HG, Murray KT. Conventional protein kinase C isoforms and cross-activation of protein kinase A regulate cardiac Na+ current. FEBS Lett. 2001 Apr 4/27/2001; 495(3): 154-8. PMID: 11334883, PII: S0014-5793(01)02380-8, ISSN: 0014-5793.
• Jeyakumar LH, Ballester L, Cheng DS, McIntyre JO, Chang P, Olivey HE, Rollins-Smith L, Barnett JV, Murray K, Xin HB, Fleischer S. FKBP binding characteristics of cardiac microsomes from diverse vertebrates. Biochem. Biophys. Res. Commun. 2001 Mar 3/9/2001; 281(4): 979-86. PMID: 11237759, PII: S0006-291X(01)94444-4, DOI: 10.1006/bbrc.2001.4444, ISSN: 0006-291X.
• Shin HG, Barnett JV, Chang P, Reddy S, Drinkwater DC, Pierson RN, Wiley RG, Murray KT. Molecular heterogeneity of protein kinase C expression in human ventricle. Cardiovasc. Res. 2000 Nov; 48(2): 285-99. PMID: 11054475, PII: S0008-6363(00)00185-1, ISSN: 0008-6363.
• Yang IC, Scherz MW, Bahinski A, Bennett PB, Murray KT. Stereoselective interactions of the enantiomers of chromanol 293B with human voltage-gated potassium channels. J. Pharmacol. Exp. Ther. 2000 Sep; 294(3): 955-62. PMID: 10945846, ISSN: 0022-3565.
• Zhou J, Yi J, Hu N, George AL, Murray KT. Activation of protein kinase A modulates trafficking of the human cardiac sodium channel in Xenopus oocytes. Circ. Res. 2000 Jul 7/7/2000; 87(1): 33-8. PMID: 10884369, ISSN: 0009-7330.
• Murray KT. Ibutilide. Circulation. 1998 Feb 2/10/1998; 97(5): 493-7. PMID: 9490245, ISSN: 0009-7322.
• Murray KT, Hu NN, Daw JR, Shin HG, Watson MT, Mashburn AB, George AL. Functional effects of protein kinase C activation on the human cardiac Na+ channel. Circ. Res. 1997 Mar; 80(3): 370-6. PMID: 9048657, ISSN: 0009-7330.
• Echt DS, Lee JT, Murray KT, Vorperian V, Borganelli SM, Crawford DM, Friedrich T, Roden DM. A randomized, double-blind, placebo-controlled, dose-ranging study of dofetilide in patients with inducible sustained ventricular tachyarrhythmias. J. Cardiovasc. Electrophysiol. 1995 Sep; 6(9): 687-99. PMID: 8556189, ISSN: 1045-3873.
• Murray KT, Fahrig SA, Deal KK, Po SS, Hu NN, Snyders DJ, Tamkun MM, Bennett PB. Modulation of an inactivating human cardiac K+ channel by protein kinase C. Circ. Res. 1994 Dec; 75(6): 999-1005. PMID: 7955154, ISSN: 0009-7330.
• Echt DS, Gremillion ST, Lee JT, Roden DM, Murray KT, Borganelli M, Crawford DM, Stewart JR, Hammon JW. Effects of procainamide and lidocaine on defibrillation energy requirements in patients receiving implantable cardioverter defibrillator devices. J. Cardiovasc. Electrophysiol. 1994 Sep; 5(9): 752-60. PMID: 7827714, ISSN: 1045-3873.
• Ware DL, Lee JT, Murray KT, Hanyok JJ, Roden DM, Echt DS. Intravenous 3-methoxy-O-desmethyl-encainide in reentrant supraventricular tachycardia: a randomized double-blind placebo-controlled trial in patients undergoing EP study. Pacing Clin Electrophysiol. 1991 Sep; 14(9): 1343-50. PMID: 1720527, ISSN: 0147-8389.
• Murray KT, Anno T, Bennett PB, Hondeghem LM. Voltage clamp of the cardiac sodium current at 37 degrees C in physiologic solutions. Biophys. J. 1990 Mar; 57(3): 607-13. PMID: 2155034, PMCID: PMC1280754, PII: S0006-3495(90)82576-5, DOI: 10.1016/S0006-3495(90)82576-5, ISSN: 0006-3495.
• Murray KT, Reilly C, Koshakji RP, Roden DM, Lineberry MD, Wood AJ, Siddoway LA, Barbey JT, Woosley RL. Suppression of ventricular arrhythmias in man by d-propranolol independent of beta-adrenergic receptor blockade. J. Clin. Invest. 1990 Mar; 85(3): 836-42. PMID: 2155929, PMCID: PMC296501, DOI: 10.1172/JCI114510, ISSN: 0021-9738.
• Murray KT, Barbey JT, Kopelman HA, Siddoway LA, Echt DS, Woosley RL, Roden DM. Mexiletine and tocainide: a comparison of antiarrhythmic efficacy, adverse effects, and predictive value of lidocaine testing. Clin. Pharmacol. Ther. 1989 May; 45(5): 553-61. PMID: 2498025, PII: 0009-9236(89)90454-2, ISSN: 0009-9236.