Electrophysiology and metabolism of caveolin-3-overexpressing mice

  • Jan M. Schilling
  • Yousuke T. Horikawa
  • Alice E. Zemljic-Harpf
  • Kevin P. Vincent
  • Leonid Tyan
  • Judith K. Yu
  • Andrew D. McCulloch
  • Ravi C. Balijepalli
  • Hemal H. Patel
  • David M. RothEmail author
Original Contribution


Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac-specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury, suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism. We examined: (1) ECG telemetry recordings at baseline and during pharmacological interventions, (2) ion channels involved in cardiac conduction with immunoblotting and computational modeling, and (3) baseline metabolism in Cav-3 OE and transgene-negative littermate control mice. Cav-3 OE mice had decreased heart rates, prolonged PR intervals, and shortened QTc intervals with no difference in activity compared to control mice. Dobutamine or propranolol did not cause significant changes between experimental groups in maximal (dobutamine) or minimal (propranolol) heart rate. Cav-3 OE mice had an overall lower chronotropic response to atropine. The expression of Kv1.4 and Kv4.3 channels, Nav1.5 channels, and connexin 43 were increased in Cav-3 OE mice. A computational model integrating the immunoblotting results indicated shortened action potential duration in Cav-3 OE mice linking the change in channel expression to the observed electrophysiology phenotype. Metabolic profiling showed no gross differences in VO2, VCO2, respiratory exchange ratio, heat generation, and feeding or drinking. In conclusion, Cav-3 OE mice have changes in ECG intervals, heart rates, and cardiac ion channel expression. These findings give novel mechanistic insights into previously reported Cav-3 dependent cardioprotection.


Caveolae Caveolin-3 Cardiac conduction Heart rate Kv channels 



A-kinase anchoring protein


Analysis of variance


Action potential duration


Beats per minute


Carbon dioxide




Calcium transients


Connexin 43




Ethylenediaminetetraacetic acid


Glyceraldehyde 3-phosphate dehydrogenase


Conductance of fast sodium channel


G-protein-coupled receptors


Conductance of fast transient outward potassium current






Slow component of transient outward potassium current




Voltage-gated potassium channel


Kv channel interacting proteins




Messenger ribonucleic acid






Voltage-gated sodium channel






Polyacrylamide gel electrophoresis


Power of hydrogen


Respiratory exchange ratio


Sodium channel, voltage-gated, type V alpha subunit


Standard deviation


Sodium dodecyl sulfate





We would like to acknowledge the technical assistance of Michael Migita in the performance of the study. The work was supported by Veteran Affairs Merit Awards from the Department of Veterans Affairs BX000783 (D. M. Roth), and BX001963 (H. H. Patel), National Institutes of Health HL105713 (R. C. Balijepalli), HL078878 (R. C. Balijepalli), HL091071 (H. H. Patel), HL107200 (H. H. Patel and D.M. Roth), HL066941 (H. H. Patel and D.M. Roth), HL115933 (H. H. Patel and D.M. Roth), GM103426 (A. D. McCulloch), HL105242 (A. D. McCulloch), and EB014593 (A. D. McCulloch). ADM is a co-founder, equity-holder, and scientific advisor to Insilicomed, Inc. This relationship is managed by a UCSD Conflict of Interest sub-committee. However, there was no involvement of Insilicomed, Inc. in the research described here. The authors have no additional financial disclosures.


  1. 1.
    Alday A, Urrutia J, Gallego M, Casis O (2010) alpha1-adrenoceptors regulate only the caveolae-located subpopulation of cardiac K(V)4 channels. Channels (Austin, Tex.) 4:168–178. doi: 10.4161/chan.4.3.11479 CrossRefGoogle Scholar
  2. 2.
    Balijepalli RC, Delisle BP, Balijepalli SY, Foell JD, Slind JK, Kamp TJ, January CT (2007) Kv11.1 (ERG1) K+ channels localize in cholesterol and sphingolipid enriched membranes and are modulated by membrane cholesterol. Channels (Austin, Tex.) 1:263–272. doi: 10.4161/chan.4946 CrossRefGoogle Scholar
  3. 3.
    Balijepalli RC, Foell JD, Hall DD, Hell JW, Kamp TJ (2006) Localization of cardiac L-type Ca(2+) channels to a caveolar macromolecular signaling complex is required for beta(2)-adrenergic regulation. Proc Natl Acad Sci USA 103:7500–7505. doi: 10.1073/pnas.0503465103 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Balijepalli RC, Kamp TJ (2008) Caveolae, ion channels and cardiac arrhythmias. Prog Biophys Mol Biol 98:149–160. doi: 10.1016/j.pbiomolbio.2009.01.012 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Barbuti A, Gravante B, Riolfo M, Milanesi R, Terragni B, DiFrancesco D (2004) Localization of pacemaker channels in lipid rafts regulates channel kinetics. Circ Res 94:1325–1331. doi: 10.1161/01.RES.0000127621.54132.AE CrossRefPubMedGoogle Scholar
  6. 6.
    Benoist D, Stones R, Drinkhill M, Bernus O, White E (2011) Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. Am J Physiol Heart Circ Physiol 300:H2230–2237. doi: 10.1152/ajpheart.01226.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bossuyt J, Taylor BE, James-Kracke M, Hale CC (2002) The cardiac sodium-calcium exchanger associates with caveolin-3. Ann N Y Acad Sci 976:197–204. doi: 10.1111/j.1749-6632.2002.tb04741.x CrossRefPubMedGoogle Scholar
  8. 8.
    Bossuyt J, Taylor BE, James-Kracke M, Hale CC (2002) Evidence for cardiac sodium-calcium exchanger association with caveolin-3. FEBS Lett 511:113–117. doi: 10.1016/S0014-5793(01)03323-3 CrossRefPubMedGoogle Scholar
  9. 9.
    Chandler NJ, Greener ID, Tellez JO, Inada S, Musa H, Molenaar P, Difrancesco D, Baruscotti M, Longhi R, Anderson RH, Billeter R, Sharma V, Sigg DC, Boyett MR, Dobrzynski H (2009) Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker. Circulation 119:1562–1575. doi: 10.1161/circulationaha.108.804369 CrossRefPubMedGoogle Scholar
  10. 10.
    Cheng J, Valdivia CR, Vaidyanathan R, Balijepalli RC, Ackerman MJ, Makielski JC (2013) Caveolin-3 suppresses late sodium current by inhibiting nNOS-dependent S-nitrosylation of SCN5A. J Mol Cell Cardiol 61:102–110. doi: 10.1016/j.yjmcc.2013.03.013 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cohen AW, Hnasko R, Schubert W, Lisanti MP (2004) Role of caveolae and caveolins in health and disease. Physiol Rev 84:1341–1379. doi: 10.1152/physrev.00046.2003 CrossRefPubMedGoogle Scholar
  12. 12.
    Conrath CE, Opthof T (2006) Ventricular repolarization: an overview of (patho)physiology, sympathetic effects and genetic aspects. Prog Biophys Mol Biol 92:269–307. doi: 10.1016/j.pbiomolbio.2005.05.009 CrossRefPubMedGoogle Scholar
  13. 13.
    Cronk LB, Ye B, Kaku T, Tester DJ, Vatta M, Makielski JC, Ackerman MJ (2007) Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm 4:161–166. doi: 10.1016/j.hrthm.2006.11.030 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dhein S, Seidel T, Salameh A, Jozwiak J, Hagen A, Kostelka M, Hindricks G, Mohr FW (2014) Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias. Front Physiol 5:424. doi: 10.3389/fphys.2014.00424 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R (2014) Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66:1142–1174. doi: 10.1124/pr.113.008300 CrossRefPubMedGoogle Scholar
  16. 16.
    Fontes, Raaijmakers AJ, van Doorn T, Kok B, Nieuwenhuis S, van der Nagel R, Vos MA, de Boer TP, van Rijen HV, Bierhuizen MF (2014) Changes in Cx43 and NaV1.5 expression precede the occurrence of substantial fibrosis in calcineurin-induced murine cardiac hypertrophy. PloS One 9:e87226. doi: 10.1371/journal.pone.0087226 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fontes MS, van Veen TA, de Bakker JM, van Rijen HV (2012) Functional consequences of abnormal Cx43 expression in the heart. Biochim Biophys Acta 1818:2020–2029. doi: 10.1016/j.bbamem.2011.07.039 CrossRefPubMedGoogle Scholar
  18. 18.
    Giusti B, Marini M, Rossi L, Lapini I, Magi A, Capalbo A, Lapalombella R, di Tullio S, Samaja M, Esposito F, Margonato V, Boddi M, Abbate R, Veicsteinas A (2009) Gene expression profile of rat left ventricles reveals persisting changes following chronic mild exercise protocol: implications for cardioprotection. BMC Genom 10:342. doi: 10.1186/1471-2164-10-342 CrossRefGoogle Scholar
  19. 19.
    Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. doi: 10.1161/circresaha.116.305348 CrossRefPubMedGoogle Scholar
  20. 20.
    Horikawa YT, Panneerselvam M, Kawaraguchi Y, Tsutsumi YM, Ali SS, Balijepalli RC, Murray F, Head BP, Niesman IR, Rieg T, Vallon V, Insel PA, Patel HH, Roth DM (2011) Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling. J Am Coll Cardiol 57:2273–2283. doi: 10.1016/j.jacc.2010.12.032 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Horikawa YT, Patel HH, Tsutsumi YM, Jennings MM, Kidd MW, Hagiwara Y, Ishikawa Y, Insel PA, Roth DM (2008) Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury. J Mol Cell Cardiol 44:123–130. doi: 10.1016/j.yjmcc.2007.10.003 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Horikawa YT, Tsutsumi YM, Patel HH, Roth DM (2014) Signaling epicenters: the role of caveolae and caveolins in volatile anesthetic induced cardiac protection. Curr Pharm Des 20:5681–5689. doi: 10.2174/1381612820666140204111236 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kannankeril PJ, Harris PA, Norris KJ, Warsy I, Smith PD, Roden DM (2008) Rate-independent QT shortening during exercise in healthy subjects: terminal repolarization does not shorten with exercise. J Cardiovasc Electrophysiol 19:1284–1288. doi: 10.1111/j.1540-8167.2008.01266.x CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kleber AG, Rudy Y (2004) Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev 84:431–488. doi: 10.1152/physrev.00025.2003 CrossRefPubMedGoogle Scholar
  25. 25.
    Krahn AD, Klein GJ, Yee R (1997) Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome? Circulation 96:1551–1556. doi: 10.1161/01.CIR.96.5.1551 CrossRefPubMedGoogle Scholar
  26. 26.
    Krahn AD, Yee R, Chauhan V, Skanes AC, Wang J, Hegele RA, Klein GJ (2002) Beta blockers normalize QT hysteresis in long QT syndrome. Am Heart J 143:528–534. doi: 10.1067/mhj.2002.120408 CrossRefPubMedGoogle Scholar
  27. 27.
    Lampert R (2012) Evaluation and management of arrhythmia in the athletic patient. Prog Cardiovasc Dis 54:423–431. doi: 10.1016/j.pcad.2012.01.002 CrossRefPubMedGoogle Scholar
  28. 28.
    Lohn M, Furstenau M, Sagach V, Elger M, Schulze W, Luft FC, Haller H, Gollasch M (2000) Ignition of calcium sparks in arterial and cardiac muscle through caveolae. Circ Res 87:1034–1039. doi: 10.1161/01.RES.87.11.1034 CrossRefPubMedGoogle Scholar
  29. 29.
    Markandeya YS, Fahey JM, Pluteanu F, Cribbs LL, Balijepalli RC (2011) Caveolin-3 regulates protein kinase A modulation of the Ca(V)3.2 (alpha1H) T-type Ca2+ channels. J Biol Chem 286:2433–2444. doi: 10.1074/jbc.M110.182550 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Markandeya YS, Phelan LJ, Woon MT, Keefe AM, Reynolds CR, August BK, Hacker TA, Roth DM, Patel HH, Balijepalli RC (2015) Caveolin-3 overexpression attenuates cardiac hypertrophy via inhibition of T-type Ca2+ current modulated by protein kinase calpha in cardiomyocytes. J Biol Chem 290:22085–22100. doi: 10.1074/jbc.M115.674945 CrossRefPubMedGoogle Scholar
  31. 31.
    Maron BJ, Pelliccia A (2006) The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death. Circulation 114:1633–1644. doi: 10.1161/CIRCULATIONAHA.106.613562 CrossRefPubMedGoogle Scholar
  32. 32.
    Mitchell GF, Jeron A, Koren G (1998) Measurement of heart rate and Q-T interval in the conscious mouse. Am J Physiol 274:H747–751PubMedGoogle Scholar
  33. 33.
    Morotti S, Edwards AG, McCulloch AD, Bers DM, Grandi E (2014) A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII. J Physiol 592:1181–1197. doi: 10.1113/jphysiol.2013.266676 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML (2000) Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 101:616–623. doi: 10.1161/01.CIR.101.6.616 CrossRefPubMedGoogle Scholar
  35. 35.
    Nerbonne JM, Kass RS (2005) Molecular physiology of cardiac repolarization. Physiol Rev 85:1205–1253. doi: 10.1152/physrev.00002.2005 CrossRefPubMedGoogle Scholar
  36. 36.
    Niwa N, Nerbonne JM (2010) Molecular determinants of cardiac transient outward potassium current (I(to)) expression and regulation. J Mol Cell Cardiol 48:12–25. doi: 10.1016/j.yjmcc.2009.07.013 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Palade G (1953) Fine structure of blood capillaries. J of Appl Phys 24:1424–1436Google Scholar
  38. 38.
    Patel HH, Murray F, Insel PA (2008) Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol 48:359–391. doi: 10.1146/annurev.pharmtox.48.121506.124841 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Patel SP, Campbell DL (2005) Transient outward potassium current, ‘Ito’, phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms. J Physiol 569:7–39. doi: 10.1113/jphysiol.2005.086223 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Pfeiffer ER, Wright AT, Edwards AG, Stowe JC, McNall K, Tan J, Niesman I, Patel HH, Roth DM, Omens JH, McCulloch AD (2014) Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing. J Mol Cell Cardiol 76:265–274. doi: 10.1016/j.yjmcc.2014.09.014 CrossRefPubMedGoogle Scholar
  41. 41.
    Razani B, Woodman SE, Lisanti MP (2002) Caveolae: from cell biology to animal physiology. Pharmacol Rev 54:431–467. doi: 10.1124/pr.54.3.431 CrossRefPubMedGoogle Scholar
  42. 42.
    Sarma JS, Venkataraman SK, Samant DR, Gadgil U (1987) Hysteresis in the human RR-QT relationship during exercise and recovery. Pacing Clin Electrophysiol PACE 10:485–491CrossRefPubMedGoogle Scholar
  43. 43.
    Scharhag J, Lollgen H, Kindermann W (2013) Competitive sports and the heart: benefit or risk? Deutsches Arzteblatt Int 110:14–23; quiz 24; e11–12 doi: 10.3238/arztebl.2013.0014
  44. 44.
    Schimpf R, Borggrefe M, Wolpert C (2008) Clinical and molecular genetics of the short QT syndrome. Curr Opin Cardiol 23:192–198. doi: 10.1097/HCO.0b013e3282fbf756 CrossRefPubMedGoogle Scholar
  45. 45.
    Schulze-Bahr E, Eckardt L, Breithardt G, Seidl K, Wichter T, Wolpert C, Borggrefe M, Haverkamp W (2003) Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum Mutat 21:651–652. doi: 10.1002/humu.9144 CrossRefPubMedGoogle Scholar
  46. 46.
    See Hoe LE, Schilling JM, Tarbit E, Kiessling CJ, Busija AR, Niesman IR, Du Toit E, Ashton KJ, Roth DM, Headrick JP, Patel HH, Peart JN (2014) Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection. Am J Physiol Heart Circ Physiol 307:H895–903. doi: 10.1152/ajpheart.00081.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Shvets E, Ludwig A, Nichols BJ (2014) News from the caves: update on the structure and function of caveolae. Curr Opin Cell Biol 29:99–106. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  48. 48.
    Shy D, Gillet L, Abriel H (2013) Cardiac sodium channel NaV1.5 distribution in myocytes via interacting proteins: the multiple pool model. Biochim Biophys Acta 1833:886–894. doi: 10.1016/j.bbamcr.2012.10.026 CrossRefPubMedGoogle Scholar
  49. 49.
    Smits JP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, Haverkamp W, Breithardt G, Escande D, Schulze-Bahr E, LeMarec H, Wilde AA (2002) Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol 40:350–356. doi: 10.1016/S0735-1097(02)01962-9 CrossRefPubMedGoogle Scholar
  50. 50.
    Smits JP, Wilde AA (2002) Brugada syndrome: in search of a genotype-phenotype relationship. Herzschrittmachertherapie Elektrophysiologie 13:142–148. doi: 10.1007/s00399-002-0350-9 CrossRefPubMedGoogle Scholar
  51. 51.
    Soetkamp D, Nguyen TT, Menazza S, Hirschhauser C, Hendgen-Cotta UB, Rassaf T, Schluter KD, Boengler K, Murphy E, Schulz R (2014) S-nitrosation of mitochondrial connexin 43 regulates mitochondrial function. Basic Res Cardiol 109:433. doi: 10.1007/s00395-014-0433-x CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Song KS, Scherer PE, Tang Z, Okamoto T, Li S, Chafel M, Chu C, Kohtz DS, Lisanti MP (1996) Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins. J Biol Chem 271:15160–15165CrossRefPubMedGoogle Scholar
  53. 53.
    Steinberg SF, Brunton LL (2001) Compartmentation of G protein-coupled signaling pathways in cardiac myocytes. Annu Rev Pharmacol Toxicol 41:751–773. doi: 10.1146/annurev.pharmtox.41.1.751 CrossRefPubMedGoogle Scholar
  54. 54.
    Sun J, Nguyen T, Aponte AM, Menazza S, Kohr MJ, Roth DM, Patel HH, Murphy E, Steenbergen C (2015) Ischaemic preconditioning preferentially increases protein S-nitrosylation in subsarcolemmal mitochondria. Cardiovasc Res 106:227–236. doi: 10.1093/cvr/cvv044 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Tsutsumi YM, Horikawa YT, Jennings MM, Kidd MW, Niesman IR, Yokoyama U, Head BP, Hagiwara Y, Ishikawa Y, Miyanohara A, Patel PM, Insel PA, Patel HH, Roth DM (2008) Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning. Circulation 118:1979–1988. doi: 10.1161/CIRCULATIONAHA.108.788331 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Tsutsumi YM, Tsutsumi R, Horikawa YT, Sakai Y, Hamaguchi E, Ishikawa Y, Yokoyama U, Kasai A, Kambe N, Tanaka K (2014) Geranylgeranylacetone protects the heart via caveolae and caveolin-3. Life Sci 101:43–48. doi: 10.1016/j.lfs.2014.02.019 CrossRefPubMedGoogle Scholar
  57. 57.
    Tsutsumi YM, Tsutsumi R, Horikawa YT, Sakai Y, Hamaguchi E, Kitahata H, Kasai A, Kambe N, Tanaka K (2014) Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3. J Anesth 28:733–739. doi: 10.1007/s00540-014-1816-8 CrossRefPubMedGoogle Scholar
  58. 58.
    Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA (2006) Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114:2104–2112. doi: 10.1161/CIRCULATIONAHA.106.635268 CrossRefPubMedGoogle Scholar
  59. 59.
    Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT (1995) SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80:805–811CrossRefPubMedGoogle Scholar
  60. 60.
    Willis BC, Ponce-Balbuena D, Jalife J (2015) Protein assemblies of sodium and inward rectifier potassium channels control cardiac excitability and arrhythmogenesis. Am J Physiol Heart Circ Physiol 308:H1463–1473. doi: 10.1152/ajpheart.00176.2015 CrossRefPubMedGoogle Scholar
  61. 61.
    Xu H, Guo W, Nerbonne JM (1999) Four kinetically distinct depolarization-activated K+ currents in adult mouse ventricular myocytes. J Gen Physiol 113:661–678. doi: 10.1085/jgp.113.5.661 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yamada E (1955) The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol 1:445–458CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Yang KC, Rutledge CA, Mao M, Bakhshi FR, Xie A, Liu H, Bonini MG, Patel HH, Minshall RD, Dudley SC Jr (2014) Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase. Circulation. Arrhythmia Electrophysiol 7:701–710. doi: 10.1161/CIRCEP.113.001394 CrossRefGoogle Scholar
  64. 64.
    Yarbrough TL, Lu T, Lee HC, Shibata EF (2002) Localization of cardiac sodium channels in caveolin-rich membrane domains: regulation of sodium current amplitude. Circ Res 90:443–449. doi: 10.1161/hh0402.105177 CrossRefPubMedGoogle Scholar
  65. 65.
    Ye B, Balijepalli RC, Foell JD, Kroboth S, Ye Q, Luo YH, Shi NQ (2008) Caveolin-3 associates with and affects the function of hyperpolarization-activated cyclic nucleotide-gated channel 4. Biochemistry 47:12312–12318. doi: 10.1021/bi8009295 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Zhang T, Yong SL, Tian XL, Wang QK (2007) Cardiac-specific overexpression of SCN5A gene leads to shorter P wave duration and PR interval in transgenic mice. Biochem Biophys Res Commun 355:444–450. doi: 10.1016/j.bbrc.2007.01.170 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Zhang Y, Wu J, King JH, Huang CL, Fraser JA (2014) Measurement and interpretation of electrocardiographic QT intervals in murine hearts. Am J Physiol Heart Circ Physiol 306:H1553–1557. doi: 10.1152/ajpheart.00459.2013 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Jan M. Schilling
    • 1
    • 2
  • Yousuke T. Horikawa
    • 3
    • 6
  • Alice E. Zemljic-Harpf
    • 1
    • 2
  • Kevin P. Vincent
    • 4
  • Leonid Tyan
    • 7
  • Judith K. Yu
    • 2
  • Andrew D. McCulloch
    • 4
    • 5
  • Ravi C. Balijepalli
    • 7
  • Hemal H. Patel
    • 1
    • 2
  • David M. Roth
    • 1
    • 2
    Email author
  1. 1.Veterans Affairs San Diego Healthcare SystemSan DiegoUSA
  2. 2.Department of AnesthesiologyUniversity of California San DiegoLa JollaUSA
  3. 3.Department of PediatricsUniversity of California San DiegoLa JollaUSA
  4. 4.Department of BioengineeringUniversity of California San DiegoLa JollaUSA
  5. 5.Department of MedicineUniversity of California San DiegoLa JollaUSA
  6. 6.Department of PediatricsSharp Rees-Stealy Medical GroupSan DiegoUSA
  7. 7.Department of Medicine, Cellular and Molecular Arrhythmia Research ProgramUniversity of WisconsinMadisonUSA

Personalised recommendations