钠离子通道与相关心脏疾病的研究进展
Research Progress in Voltage-Gated Sodium Channels and Related Cardiac Diseases
DOI: 10.12677/HJBM.2020.104014, PDF,    科研立项经费支持
作者: 徐艺珈, 孙健芳, 韩雨诺, 赵明沂*：沈阳药科大学，生命科学与生物制药学院，辽宁 沈阳
关键词: 电压门控钠离子通道；Nav1.5；Nav1.8；心律失常；心脏疾病；心脏毒性；Voltage Gated Sodium Channels； Nav1.5； Nav1.8； Arrhythmia； Cardiac disease； Cardiac Toxicity
摘要: 电压门控钠离子通道广泛分布于可兴奋细胞的细胞膜上，参与动作电位的产生及传导，主要负责调控动作电位的初始上升相。钠离子通道是最重要的心脏离子通道之一，分布于窦房结、传导系统、心房肌和心室肌，是一类抗心律失常药物的靶蛋白。心脏钠通道的表达正常与否直接影响到心脏的生理病理功能，其功能获得性和功能缺失性的突变均会导致相关心脏疾病的发生。本文阐述了心脏钠离子通道(Nav1.5和Nav1.8)的结构及功能，以及通道异常表达时相关疾病的研究现状，为药物临床应用前的心脏毒性研究及心血管药物的研究开发和临床应用提供重要的理论依据。
Abstract: Voltage gated sodium channels (VGSCs) are transmembrane proteins responsible for the initial and rapid phase of the action potential in most electrically excitable cells. VGSCs are the most important cardiac ion channels, which are widely located in highly expressed in all types of cardiac myocytes, including the sinus node, the conduction system, atrial and ventricular myocytes. VGSCs are target proteins of type 1 anti-arrhythmic drugs. The expression of cardiac VGSCs may affect the physiological and pathological functions of cardiac. Gain-of-function mutations and loss-of-function mutations of cardiac VGSCs may cause several cardiac diseases. In this article, we focused on reviewing the structure, function and related diseases of cardiac VGSCs (Nav1.5 and Nav1.8), in hopes of providing a reference for further in-depth research regarding relevant drug cardiotoxicity before clinical applications and cardiovascular drug discovery.

文章引用：徐艺珈, 孙健芳, 韩雨诺, 赵明沂. 钠离子通道与相关心脏疾病的研究进展[J]. 生物医学, 2020, 10(4): 103-109. https://doi.org/10.12677/HJBM.2020.104014

参考文献

[1] Ekberg, J. and Adams, D.J. (2006) Neuronal Voltage-Gated Sodium Channel Subtypes: Key Roles in Inflammatory and Neuropathic Pain. Int J Biochem Cell Biol., 38, 2005-2010. [Google Scholar] [CrossRef] [PubMed]
[2] Payandeh, J., Gamal El-Din, T.M., Scheuer, T., et al. (2012) Crystal Structure of a Voltage-Gated Sodium Channel in Two Potentially Inactivated States. Nature, 486, 135-139. [Google Scholar] [CrossRef] [PubMed]
[3] Blechschmidt, S., Haufe, V., Benndorf, K., et al. (2008) Voltage-Gated Na+ Channel Transcript Patterns in the Mammalian Heart Are Species-Dependent. Prog Biophys Mol Biol, 98, 309-318. [Google Scholar] [CrossRef] [PubMed]
[4] Thakor, D.K., Lin, A., Matsuka, Y., et al. (2009) Increased Peripheral Nerve Excitability and Local NaV1.8 mRNA Up-Regulation in Painful Neuropathy. Mol Pain, 5, 14. [Google Scholar] [CrossRef] [PubMed]
[5] Coward, K., Plumpton, C., Facer, P., et al. (2000) Immunolocalization of SNS/PN3 and NaN/SNS2 Sodium Channels in Human Pain States. Pain, 85, 41-50. [Google Scholar] [CrossRef] 
[6] Verkerk, A.O., Remme, C.A., Schumacher, C.A., et al. (2012) Functional Nav1.8 Channels in Intracardiac Neurons: The Link between SCN10A and Cardiac Electrophysiology. Circ Res., 111, 333-343. [Google Scholar] [CrossRef] 
[7] Facer, P., Punjabi, P.P., Abrari, A., et al. (2011) Localisation of SCN10A Gene Product Na(v)1.8 and Novel Pain-Related Ion Channels in Human Heart. International Heart Journal, 52, 146-152. [Google Scholar] [CrossRef] [PubMed]
[8] van den Boogaard, M., Smemo, S., Burnicka-Turek, O., et al. (2014) A Common Genetic Variant within SCN10A Modulates Cardiac SCN5A Expression. J Clin Invest, 124, 1844-1852. [Google Scholar] [CrossRef] 
[9] Yang, T., Atack, T.C., Stroud, D.M., et al. (2012) Blocking Scn10a Channels in Heart Reduces Late Sodium Current and Is Antiarrhythmic. Circ Res., 111, 322-332. [Google Scholar] [CrossRef] 
[10] Chambers, J.C., Zhao, J., Terracciano, C.M., et al. (2010) Genetic Variation in SCN10A Influences Cardiac Conduction. Nat Genet., 42, 149-152. [Google Scholar] [CrossRef] [PubMed]
[11] Crotti, L., Celano, G., Dagradi, F., et al. (2008) Congenital Long QT Syndrome. Orphanet J Rare Dis., 3, 18. [Google Scholar] [CrossRef] [PubMed]
[12] Clancy, C.E., Tateyama, M., Liu, H., et al. (2003) Non-Equilibrium Gating in Cardiac Na+ Channels: An Original Mechanism of Arrhythmia. Circulation, 107, 2233-2237. [Google Scholar] [CrossRef] 
[13] Wang, D.W., Yazawa, K., George Jr., A.L., et al. (1996) Characterization of Human Cardiac Na+ Channel Mutations in the Congenital Long QT Syndrome. Proc Natl Acad Sci USA, 93, 13200-13205. [Google Scholar] [CrossRef] [PubMed]
[14] Makita, N., Behr, E., Shimizu, W., et al. (2008) The E1784K Mutation in SCN5A Is Associated with Mixed Clinical Phenotype of Type 3 Long QT Syndrome. J Clin Invest., 118, 2219-2229. [Google Scholar] [CrossRef] 
[15] Kanters, J.K., Yuan, L., Hedley, P.L., et al. (2014) Flecainide Provocation Reveals Concealed Brugada Syndrome in a Long QT Syndrome Family with a Novel L1786Q Mutation in SCN5A. Circ J., 78, 1136-1143. [Google Scholar] [CrossRef] 
[16] Song, W. and Shou, W. (2012) Cardiac Sodium Channel Nav1.5 Mutations and Cardiac Arrhythmia. Pediatr Cardiol., 33, 943-949. [Google Scholar] [CrossRef] [PubMed]
[17] Wilde, A.A., Antzelevitch, C., Borggrefe, M., Brugada, J., Bru-gada, R., Brugada, P., et al. (2002) Proposed Diagnostic Criteria for the Brugada Syndrome: Consensus Report. Circulation, 106, 2514-2519. [Google Scholar] [CrossRef] 
[18] Wilde, A.A., Postema, P.G., Di Diego, J.M., et al. (2010) The Pathophysiological Mechanism Underlying Brugada Syndrome: Depolarization versus Repolarization. J Mol Cell Cardiol., 49, 543-553. [Google Scholar] [CrossRef] [PubMed]
[19] Moreau, A., Keller, D.I., Huang, H., et al. (2012) Mexiletine Differentially Restores the Trafficking Defects Caused by Two Brugada Syndrome Mutations. Front Pharmacol., 3, 62. [Google Scholar] [CrossRef] [PubMed]
[20] Ortiz-Bonnin, B., Rinné, S., Moss, R., et al. (2016) Elec-trophysiological Characterization of a Large Set of Novel Variants in the SCN5A-Gene: Identification of Novel LQTS3 and BrS Mutations. Pflugers Arch., 468, 1375-1387. [Google Scholar] [CrossRef] [PubMed]
[21] Veltmann, C., Barajas-Martinez, H., Wolpert, C., et al. (2016) Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect. J Am Heart Assoc., 5, pii: e003379. [Google Scholar] [CrossRef] 
[22] Samani, K., Wu, G., Ai, T., et al. (2009) A Novel SCN5A Mutation V1340I in Brugada Syndrome Augmenting Arrhythmias during Febrile Illness. Heart Rhythm., 6, 1318-1326. [Google Scholar] [CrossRef] [PubMed]
[23] Hu, D., Barajas-Martínez, H., Pfeiffer, R., et al. (2014) Mutations in SCN10A Are Responsible for a Large Fraction of Cases of Brugada Syndrome. J Am Coll Cardiol., 64, 66-79. [Google Scholar] [CrossRef] [PubMed]
[24] Benson, D.W., Wang, D.W., Dyment, M., et al. (2003) Congenital Sick Sinus Syndrome Caused by Recessive Mutations in the Cardiac Sodium Channel Gene (SCN5A). J Clin Invest., 112, 1019-1028. [Google Scholar] [CrossRef] 
[25] Adán, V. and Crown, L.A. (2003) Diagnosis and Treatment of Sick Sinus Syndrome. Am Fam Physician., 67, 1725-1732.
[26] Veldkamp, M.W., Wilders, R., Baartscheer, A., et al. (2003) Contribution of Sodium Channel Mutations to Bradycardia and Sinus Node Dysfunction in LQT3 Families. Circ Res., 92, 976-983. [Google Scholar] [CrossRef] 
[27] Gregoratos, G. (2003) Cardiology Patient Pages. Sick Sinus Syndrome. Circulation, 108, e143-144. [Google Scholar] [CrossRef] 
[28] Kawaguchi, T., Hayashi, H., Miyamoto, A., et al. (2013) Prognostic Implications of Progressive Cardiac Conduction Disease. Circ J., 77, 60-67. [Google Scholar] [CrossRef] 
[29] Probst, V., Kyndt, F., Potet, F., et al. (2003) Haploinsufficiency in Combination with Aging Causes SCN5A-Linked Hereditary Lenègre Disease. J Am Coll Cardiol., 41, 643-652. [Google Scholar] [CrossRef] 
[30] Meregalli, P.G., Tan, H.L., Probst, V., et al. (2009) Type of SCN5A Mutation Determines Clinical Severity and Degree of Conduction Slowing in Loss-of-Function Sodium Channelopathies. Heart Rhythm., 6, 341-348. [Google Scholar] [CrossRef] [PubMed]
[31] Sanbe, A. (2013) Dilated Cardiomyopathy: A Disease of the Myocardium. Biol Pharm Bull., 36, 18-22. [Google Scholar] [CrossRef] [PubMed]
[32] Olson, T.M., Michels, V.V., Ballew, J.D., et al. (2005) Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation. JAMA, 293, 447-454. [Google Scholar] [CrossRef] [PubMed]
[33] McNair, W.P., Sinagra, G., Taylor, M.R., et al. (2011) SCN5A Mu-tations Associate with Arrhythmic Dilated Cardiomyopathy and Commonly Localize to the Voltage-Sensing Mechanism. J Am Coll Cardiol., 57, 2160-2168. [Google Scholar] [CrossRef] [PubMed]
[34] Moreau, A., Gosselin-Badaroudine, P., Delemotte, L., et al. (2015) Gating Pore Currents Are Defects in Common with Two Nav1.5 Mutations in Patients with Mixed Arrhythmias and Dilated Cardiomyopathy. J Gen Physiol., 145, 93-106. [Google Scholar] [CrossRef] [PubMed]
[35] Gosselin-Badaroudine, P., Keller, D.I., Huang, H., et al. (2012) A Proton Leak Current through the Cardiac Sodium Channel Is Linked to Mixed Arrhythmia and the Dilated Cardiomyopathy Phenotype. PLoS ONE, 7, e38331. [Google Scholar] [CrossRef] [PubMed]

为你推荐