Cavβ2 transcription start site variants modulate calcium handling in newborn rat cardiomyocytes

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• 作者：Cristian Moreno ; Tamara Hermosilla…
• 关键词：Calcium transients ; Auxiliary subunits ; Cardiomyocytes ; L ; type calcium current
• 刊名：Pfl篓鹿gers Archiv - European Journal of Physiology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：467
• 期：12
• 页码：2473-2484
• 全文大小：832 KB
• 参考文献：1.Altier C, Garcia-Caballero A, Simms B, You H, Chen L, Walcher J, Tedford HW, Hermosilla T, Zamponi GW (2011) The Cavbeta subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels. Nat Neurosci 14:173-80. doi:10.-038/?nn.-712 CrossRef PubMed
  2.Benitah JP, Alvarez JL, Gomez AM (2010) L-type Ca(2+) current in ventricular cardiomyocytes. J Mol Cell Cardiol 48:26-6. doi:10.-016/?j.?yjmcc.-009.-7.-26 CrossRef PubMed
  3.Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198-05. doi:10.-038/-15198a CrossRef PubMed
  4.Bers DM (2006) Altered cardiac myocyte Ca regulation in heart failure. Physiology 21:380-87. doi:10.-152/?physiol.-0019.-006 CrossRef PubMed
  5.Buraei Z, Yang J (2010) The beta subunit of voltage-gated Ca2+ channels. Physiol Rev 90:1461-506. doi:10.-152/?physrev.-0057.-009 PubMedCentral CrossRef PubMed
  6.Cingolani E, Ramirez Correa GA, Kizana E, Murata M, Cho HC, Marban E (2007) Gene therapy to inhibit the calcium channel beta subunit: physiological consequences and pathophysiological effects in models of cardiac hypertrophy. Circ Res 101:166-75. doi:10.-161/?CIRCRESAHA.-07.-55721 CrossRef PubMed
  7.Colecraft HM, Alseikhan B, Takahashi SX, Chaudhuri D, Mittman S, Yegnasubramanian V, Alvania RS, Johns DC, Marban E, Yue DT (2002) Novel functional properties of Ca(2+) channel beta subunits revealed by their expression in adult rat heart cells. J Physiol 541:435-52PubMedCentral CrossRef PubMed
  8.Chen X, Nakayama H, Zhang X, Ai X, Harris DM, Tang M, Zhang H, Szeto C, Stockbower K, Berretta RM, Eckhart AD, Koch WJ, Molkentin JD, Houser SR (2011) Calcium influx through Cav1.2 is a proximal signal for pathological cardiomyocyte hypertrophy. J Mol Cell Cardiol 50:460-70. doi:10.-016/?j.?yjmcc.-010.-1.-12 PubMedCentral CrossRef PubMed
  9.Chen X, Piacentino V 3rd, Furukawa S, Goldman B, Margulies KB, Houser SR (2002) L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices. Circ Res 91:517-24CrossRef PubMed
  10.Chen X, Zhang X, Kubo H, Harris DM, Mills GD, Moyer J, Berretta R, Potts ST, Marsh JD, Houser SR (2005) Ca2+ influx-induced sarcoplasmic reticulum Ca2+ overload causes mitochondrial-dependent apoptosis in ventricular myocytes. Circ Res 97:1009-017. doi:10.-161/-1.?RES.-000189270.-2915.?D1 CrossRef PubMed
  11.Chu PJ, Larsen JK, Chen CC, Best PM (2004) Distribution and relative expression levels of calcium channel beta subunits within the chambers of the rat heart. J Mol Cell Cardiol 36:423-34. doi:10.-016/?j.?yjmcc.-003.-2.-12 CrossRef PubMed
  12.Dobrev D, Voigt N, Wehrens XH (2011) The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc Res 89:734-43. doi:10.-093/?cvr/?cvq324 PubMedCentral CrossRef PubMed
  13.Escobar AL, Ribeiro-Costa R, Villalba-Galea C, Zoghbi ME, Perez CG, Mejia-Alvarez R (2004) Developmental changes of intracellular Ca2+ transients in beating rat hearts. Am J Physiol Heart Circ Physiol 286:H971–H978. doi:10.-152/?ajpheart.-0308.-003 CrossRef PubMed
  14.Fabiato A (1983) Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245:C1–C14PubMed
  15.Fang K, Colecraft HM (2011) Mechanism of auxiliary beta-subunit-mediated membrane targeting of L-type (Ca(V)1.2) channels. J Physiol 589:4437-455. doi:10.-113/?jphysiol.-011.-14247 PubMedCentral CrossRef PubMed
  16.Fatkin D, McConnell BK, Mudd JO, Semsarian C, Moskowitz IG, Schoen FJ, Giewat M, Seidman CE, Seidman JG (2000) An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. J Clin Invest 106:1351-359. doi:10.-172/?JCI11093 PubMedCentral CrossRef PubMed
  17.Foell JD, Balijepalli RC, Delisle BP, Yunker AM, Robia SL, Walker JW, McEnery MW, January CT, Kamp TJ (2004) Molecular heterogeneity of calcium channel beta-subunits in canine and human heart: evidence for differential subcellular localization. Physiol Genomics 17:183-00. doi:10.-152/?physiolgenomics.-0207.-003 CrossRef PubMed
  18.Goonasekera SA, Hammer K, Auger-Messier M, Bodi I, Chen X, Zhang H, Reiken S, Elrod JW, Correll RN, York AJ, Sargent MA, Hofmann F, Moosmang S, Marks AR, Houser SR, Bers DM, Molkentin JD (2012) Decreased cardiac L-type Ca(2)(+) channel activity induces hypertrophy and heart failure in mice. J Clin Invest 122:280-90. doi:10.-172/?JCI58227 PubMedCentral CrossRef PubMed
  19.Haase H, Pfitzmaier B, McEnery MW, Morano I (2000) Expression of Ca(2+) channel subunits during cardiac ontogeny in mice and rats: identification of fetal alpha(1C) and beta subunit isoforms. J Cell Biochem 76:695-03CrossRef PubMed
  20.Harary I, Farley B (1960) In vitro studies of single isolated beating heart cells. Science 131:1674-675CrossRef PubMed
  21.Hermosilla T, Moren
• 作者单位：Cristian Moreno (1)
  Tamara Hermosilla (1)
  Danna Morales (1)
  Matías Encina (1)
  Leandro Torres-Díaz (1)
  Pablo Díaz (1)
  Daniela Sarmiento (2)
  Felipe Simon (2) (3)
  Diego Varela (1)
  
  1. Centro de Estudios Moleculares de la Célula (CEMC), Programa de Fisiopatología, Facultad de Medicina, ICBM, Universidad de Chile, Santiago, Chile
  2. Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Avenida Republica 239, Santiago, Chile
  3. Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
  
• 刊物主题：Human Physiology;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-2013

文摘

In the heart, the main pathway for calcium influx is mediated by L-type calcium channels, a multi-subunit complex composed of the pore-forming subunit Ca_V1.2 and the auxiliary subunits Ca_Vα₂δ₁ and Ca_Vβ₂. To date, five distinct Ca_Vβ₂ transcriptional start site (TSS) variants (Ca_Vβ_2a-e) varying only in the composition and length of the N-terminal domain have been described, each of them granting distinct biophysical properties to the L-type current. However, the physiological role of these variants in Ca2+ handling in the native tissue has not been explored. Our results show that four of these variants are present in neonatal rat cardiomyocytes. The contribution of those Ca_Vβ₂ TSS variants on endogenous L-type current and Ca2+ handling was explored by adenoviral-mediated overexpression of each Ca_Vβ₂ variant in cultured newborn rat cardiomyocytes. As expected, all Ca_Vβ₂ TSS variants increased L-type current density and produced distinctive changes on L-type calcium channel (LTCC) current activation and inactivation kinetics. The characteristics of the induced calcium transients were dependent on the TSS variant overexpressed. Moreover, the amplitude of the calcium transients varied depending on the subunit involved, being higher in cardiomyocytes transduced with Ca_Vβ_2a and smaller in Ca_Vβ_2d. Interestingly, the contribution of Ca2+ influx and Ca2+ release on total calcium transients, as well as the sarcoplasmic calcium content, was found to be TSS-variant-dependent. Remarkably, determination of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) messenger RNA (mRNA) abundance and cell size change indicates that Ca_Vβ₂ TSS variants modulate the cardiomyocyte hypertrophic state. In summary, we demonstrate that expression of individual Ca_Vβ₂ TSS variants regulates calcium handling in cardiomyocytes and, consequently, has significant repercussion in the development of hypertrophy. Keywords Calcium transients Auxiliary subunits Cardiomyocytes L-type calcium current