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Heterogeneous functional expression of the sustained inward Na+ current in guinea pig sinoatrial node cells

  • Ion channels, receptors and transporters
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A Correction to this article was published on 26 February 2018

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Abstract

The sustained inward Na+ current (I st) identified in the sinoatrial node (SAN) cell has been suggested to play a pivotal role in cardiac pacemaking. However, the composition of cells in the SAN is heterogeneous and cell-to-cell variability in the magnitude of I st remains to be fully characterized. The present study investigated the current density of I st in morphologically different types of pacemaker cells dissociated from guinea pig SAN. I st was preferentially detected in spontaneously active spindle or spider-shaped cells, but was less well expressed in larger-sized elongated spindle-type cells and practically absent in clearly striated atrial-like cells, despite clear expression of the funny current (I f). The current density of I st in spindle and spider cells varied from 0.7 to 1.6 pA pF−1 and was significantly reduced in non-beating cells with similar morphologies. By linear regression analysis, we identified a positive correlation between the current densities of I st and the L-type Ca2+ current (I Ca,L), which was specifically observed in spindle and spider cells. These cells exhibited a more negative voltage for half maximal I Ca,L activation than atrial-like cells, suggesting a variable ratio between CaV1.2- and CaV1.3-mediated I Ca,L in SAN cells. Consistent single-cell transcript measurements confirmed a higher relative expression of CaV1.3, which activates at more negative potentials, in spindle cells than in atrial-like cells. Taken together, these results can be interpreted as indicating that I st plays a specific role in primary pacemaker cells and that its presence is closely correlated with functional levels of CaV1.3-mediated I Ca,L.

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Change history

  • 26 February 2018

    Dr. Wei-Guang Ding’s given name and family name were inadvertently interchanged initially. The correct names are as shown above.

Abbreviations

I Ca,L :

L-type Ca2+ current

I f :

Hyperpolarization-activated cation current

I st :

Sustained inward current

SAN:

Sinoatrial node

References

  1. Baig SM, Koschak A, Lieb A, Gebhart M, Dafinger C, Nürnberg G, Ali A, Ahmad I, Sinnegger-Brauns MJ, Brandt N, Engel J, Mangoni ME, Farooq M, Khan HU, Nurnberg P, Striessnig J, Bolz HJ (2011) Loss of CaV1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat Neurosci 14(1):77–84. https://doi.org/10.1038/nn.2694

    Article  CAS  PubMed  Google Scholar 

  2. Benitah JP, Gomez AM, Bailly P, Da Ponte JP, Berson G, Delgado C, Lorente P (1993) Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts. J Physiol 469(1):111–138. https://doi.org/10.1113/jphysiol.1993.sp019807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Boyett MR, Honjo H, Kodama I (2000) The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 47(4):658–687. https://doi.org/10.1016/S0008-6363(00)00135-8

    Article  CAS  PubMed  Google Scholar 

  4. Chien AJ, Zhao X, Shirokov RE, Puri TS, Chang CF, Sun D, Rios E, Hosey MM (1995) Roles of a membrane-localized beta subunit in the formation and targeting of functional L-type Ca2+ channels. J Biol Chem 270(50):30036–30044

    Article  CAS  PubMed  Google Scholar 

  5. Cho HS, Takano M, Noma A (2003) The electrophysiological properties of spontaneously beating pacemaker cells isolated from mouse sinoatrial node. J Physiol 550(1):169–180. https://doi.org/10.1113/jphysiol.2003.040501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Denyer JC, Brown HF (1990) Rabbit sino-atrial node cells: isolation and electrophysiological properties. J Physiol 428(1):405–424. https://doi.org/10.1113/jphysiol.1990.sp018219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guo J, Mitsuiye T, Noma A (1997) The sustained inward current in sino-atrial node cells of guinea-pig heart. Pflugers Arch 433(4):390–396. https://doi.org/10.1007/s004240050293

    Article  CAS  PubMed  Google Scholar 

  8. Guo J, Ono K, Noma A (1995) A sustained inward current activated at the diastolic potential range in rabbit sino-atrial node cells. J Physiol 483(1):1–13. https://doi.org/10.1113/jphysiol.1995.sp020563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guo J, Ono K, Noma A (1996) Monovalent cation conductance of the sustained inward current in rabbit sinoatrial node cells. Pflugers Arch 433(1-2):209–211. https://doi.org/10.1007/s004240050269

    Article  CAS  PubMed  Google Scholar 

  10. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391(2):85–100. https://doi.org/10.1007/BF00656997

    Article  CAS  PubMed  Google Scholar 

  11. Himeno Y, Toyoda F, Satoh H, Amano A, Cha CY, Matsuura H, Noma A (2011) Minor contribution of cytosolic Ca2+ transients to the pacemaker rhythm in guinea pig sinoatrial node cells. Am J Physiol Heart Circ Physiol 300(1):H251–H261. https://doi.org/10.1152/ajpheart.00764.2010

    Article  CAS  PubMed  Google Scholar 

  12. Honjo H, Boyett MR, Coppen SR, Takagishi Y, Opthof T, Severs NJ, Kodama I (2002) Heterogeneous expression of connexins in rabbit sinoatrial node cells: correlation between connexin isotype and cell size. Cardiovasc Res 53(1):89–96. https://doi.org/10.1016/S0008-6363(01)00421-7

    Article  CAS  PubMed  Google Scholar 

  13. Honjo H, Boyett MR, Kodama I, Toyama J (1996) Correlation between electrical activity and the size of rabbit sino-atrial node cells. J Physiol 496(3):795–808. https://doi.org/10.1113/jphysiol.1996.sp021728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kodama I, Nikmaram MR, Boyett MR, Suzuki R, Honjo H, Owen JM (1997) Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node. Am J Phys 272:H2793–H2806

    CAS  Google Scholar 

  15. Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, Striessnig J (2001) α1D (Cav1.3) subunits can form L-type Ca2+ channels activating at negative voltages. J Biol Chem 276(25):22100–22106. https://doi.org/10.1074/jbc.M101469200

    Article  CAS  PubMed  Google Scholar 

  16. Lei M, Honjo H, Kodama I, Boyett MR (2001) Heterogeneous expression of the delayed-rectifier K+ currents i K,r and i K,s in rabbit sinoatrial node cells. J Physiol 535(3):703–714. https://doi.org/10.1111/j.1469-7793.2001.t01-1-00703.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mangoni ME, Couette B, Bourinet E, Platzer J, Reimer D, Striessnig J, Nargeot J (2003) Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc Natl Acad Sci U S A 100(9):5543–5548. https://doi.org/10.1073/pnas.0935295100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mangoni ME, Nargeot J (2008) Genesis and regulation of the heart automaticity. Physiol Rev 88(3):919–982. https://doi.org/10.1152/physrev.00018.2007

    Article  CAS  PubMed  Google Scholar 

  19. Mangoni ME, Nargeot J (2001) Properties of the hyperpolarization-activated current (I f) in isolated mouse sino-atrial cells. Cardiovasc Res 52(1):51–64. https://doi.org/10.1016/S0008-6363(01)00370-4

    Article  CAS  PubMed  Google Scholar 

  20. Matsuura H, Ehara T, Ding WG, Omatsu-Kanbe M, Isono T (2002) Rapidly and slowly activating components of delayed rectifier K+ current in guinea-pig sino-atrial node pacemaker cells. J Physiol 540(3):815–830. https://doi.org/10.1113/jphysiol.2001.016741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mitsuiye T, Shinagawa Y, Noma A (2000) Sustained inward current during pacemaker depolarization in mammalian sinoatrial node cells. Circ Res 87(2):88–91. https://doi.org/10.1161/01.RES.87.2.88

    Article  CAS  PubMed  Google Scholar 

  22. Musa H, Lei M, Honjo H, Jones SA, Dobrzynski H, Lancaster MK, Takagishi Y, Henderson Z, Kodama I, Boyett MR (2002) Heterogeneous expression of Ca2+ handling proteins in rabbit sinoatrial node. J Histochem Cytochem 50(3):311–324. https://doi.org/10.1177/002215540205000303

    Article  CAS  PubMed  Google Scholar 

  23. Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, Zheng H, Striessnig J (2000) Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102(1):89–97. https://doi.org/10.1016/S0092-8674(00)00013-1

    Article  CAS  PubMed  Google Scholar 

  24. Santoro B, Wainger BJ, Siegelbaum SA (2004) Regulation of HCN channel surface expression by a novel C-terminal protein-protein interaction. J Neurosci 24(47):10750–10762. https://doi.org/10.1523/JNEUROSCI.3300-04.2004

    Article  CAS  PubMed  Google Scholar 

  25. Shinagawa Y, Satoh H, Noma A (2000) The sustained inward current and inward rectifier K+ current in pacemaker cells dissociated from rat sinoatrial node. J Physiol 523(3):593–605. https://doi.org/10.1111/j.1469-7793.2000.t01-2-00593.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G, Berjukov S, Cavalli M, Walter D, Koschak A, Waldschutz R, Hering S, Bova S, Rorsman P, Pongs O, Singewald N, Striessnig JJ (2004) Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca2+ channels. J Clin Invest 113(10):1430–1439. https://doi.org/10.1172/JCI20208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Torrente AG, Mesirca P, Neco P, Rizzetto R, Dubel S, Barrere C, Sinegger-Brauns M, Striessnig J, Richard S, Nargeot J, Gomez AM, Mangoni ME (2016) L-type Cav1.3 channels regulate ryanodine receptor-dependent Ca2+ release during sino-atrial node pacemaker activity. Cardiovasc Res 109(3):451–461. https://doi.org/10.1093/cvr/cvw006

    Article  CAS  PubMed  Google Scholar 

  28. Toyoda F, Ding WG, Matsuura H (2005) Responses of the sustained inward current to autonomic agonists in guinea-pig sino-atrial node pacemaker cells. Br J Pharmacol 144(5):660–668. https://doi.org/10.1038/sj.bjp.0706101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Toyoda F, Mesirca P, Dubel S, Ding WG, Striessnig J, Mangoni ME, Matsuura H (2017) CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current. Sci Rep 7(1):7869. https://doi.org/10.1038/s41598-017-08191-8

    Article  PubMed  PubMed Central  Google Scholar 

  30. Verheijck EE, Wessels A, van Ginneken AC, Bourier J, Markman MW, Vermeulen JL, de Bakker JM, Lamers WH, Opthof T, Bouman LN (1998) Distribution of atrial and nodal cells within the rabbit sinoatrial node: models of sinoatrial transition. Circulation 97(16):1623–1631. https://doi.org/10.1161/01.CIR.97.16.1623

    Article  CAS  PubMed  Google Scholar 

  31. Wu J, Schuessler RB, Rodefeld MD, Saffitz JE, Boineau JP (2001) Morphological and membrane characteristics of spider and spindle cells isolated from rabbit sinus node. Am J Physiol Heart Circ Physiol 280(3):H1232–H1240

    Article  CAS  PubMed  Google Scholar 

  32. Xie Y, Ding WG, Matsuura H (2015) Ca2+/calmodulin potentiates I Ks in sinoatrial node cells by activating Ca2+/calmodulin-dependent protein kinase II. Pflugers Arch 467(2):241–251. https://doi.org/10.1007/s00424-014-1507-1

    Article  CAS  PubMed  Google Scholar 

  33. Yamamoto M, Honjo H, Niwa R, Kodama I (1998) Low-frequency extracellular potentials recorded from the sinoatrial node. Cardiovasc Res 39(2):360–372. https://doi.org/10.1016/S0008-6363(98)00091-1

    Article  CAS  PubMed  Google Scholar 

  34. Zhang Z, Xu Y, Song H, Rodriguez J, Tuteja D, Namkung Y, Shin HS, Chiamvimonvat N (2002) Functional roles of Cav1.3 (α1D) calcium channel in sinoatrial nodes: insight gained using gene-targeted null mutant mice. Circ Res 90(9):981–987. https://doi.org/10.1161/01.RES.0000018003.14304.E2

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Dr. Matteo E. Mangoni and Dr. Jeorg Striessnig for fruitful discussions and encouragement.

Funding

The project was supported by the Grant-in-Aid for Scientific Research (C) 23590258, 26460295 and 17K08537 from the Japan Society for the Promotion of Science (to F.T.).

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Contributions

F.T., D. W-G., and H.M. designed the study. F.T. performed all experiments and analyzed the data. F.T. drafted the manuscript and all authors critically revised it for technical and important contents.

Corresponding author

Correspondence to Futoshi Toyoda.

Additional information

A correction to this article is available online at https://doi.org/10.1007/s00424-018-2129-9.

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Toyoda, F., Wei-Guang, D. & Matsuura, H. Heterogeneous functional expression of the sustained inward Na+ current in guinea pig sinoatrial node cells. Pflugers Arch - Eur J Physiol 470, 481–490 (2018). https://doi.org/10.1007/s00424-017-2091-y

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