Toward an Understanding of the Complete NCX1 Lifetime in the Cardiac Sarcolemma

  • Donald W. HilgemannEmail author
  • Mei-Jung Lin
  • Michael Fine
  • Gary Frazier
  • Hao-Ran Wang
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 961)


The density of Na/Ca exchangers (NCX1) in the cardiac sarcolemma, like all plasma membrane proteins, will be influenced by (and ultimately determined by) the function of membrane insertion and retrieval processes (i.e., exo- and endocytic mechanisms). Progress in understanding these processes in cardiac muscle faces many biological and methodological complexities and hurdles. As described here, we are attempting to overcome these hurdles to study more adequately the assembly and disassembly of the cardiac sarcolemma, in general, and the control of NCX1 by membrane trafficking processes in particular. First, we have developed improved noninvasive methods to monitor the cellular capacitance of cardiac tissue (NIC) over periods of hours. Thus, we can study long-term changes of total membrane area. Second, we have developed mice that express fusion proteins of NCX1 with the pHluorin green protein. Thus, we can determine the membrane disposition of NCX1, and changes thereof, on-line in intact cardiac muscle.


Cardiac sarcolemma NCX1 Electrophysiology Endocytosis Exocytosis 


  1. J.M. Best, J.D. Foell, C.R. Buss, B.P. Delisle, R.C. Balijepalli, C.T. January, T.J. Kamp, The small GTPase Rab11b regulates degradation of surface membrane L-type Cav1.2 channels. Am. J. Physiol. Cell Physiol. 300, C1023–C1033 (2011)PubMedCrossRefGoogle Scholar
  2. J. Chen, J. Sroubek, Y. Krishnan, Y. Li, J. Bian, T.V. McDonald, PKA phosphorylation of HERG protein regulates the rate of channel synthesis. Am. J. Physiol. Heart Circ. Physiol. 296, H1244–H1254 (2009)PubMedCrossRefGoogle Scholar
  3. F.S. Cusdin, J.J. Clare, A.P. Jackson, Trafficking and cellular distribution of voltage-gated sodium channels. Traffic 9, 17–26 (2008)PubMedCrossRefGoogle Scholar
  4. G.J. Doherty, H.T. McMahon, Mechanisms of endocytosis. Annu. Rev. Biochem. 78, 857–902 (2009)PubMedCrossRefGoogle Scholar
  5. J.G. Donaldson, N. Porat-Shliom, L.A. Cohen, Clathrin-independent endocytosis: a unique platform for cell signaling and PM remodeling. Cell. Signal. 21, 1–6 (2009)PubMedCrossRefGoogle Scholar
  6. D.J. Fazakerley, S.P. Lawrence, V.A. Lizunov, S.W. Cushman, G.D. Holman, A common trafficking route for GLUT4 in cardiomyocytes in response to insulin, contraction and energy-status signalling. J. Cell Sci. 122, 727–734 (2009)PubMedCrossRefGoogle Scholar
  7. S.M. Ferguson, G. Brasnjo, M. Hayashi, M. Wolfel, C. Collesi, S. Giovedi, A. Raimondi, L.W. Gong, P. Ariel, S. Paradise, E. O’Toole, R. Flavell, O. Cremona, G. Miesenbock, T.A. Ryan, P. De Camilli, A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science 316, 570–574 (2007)PubMedCrossRefGoogle Scholar
  8. M. Fine, M.C. Llaguno, V. Lariccia, M.J. Lin, A. Yaradanakul, D.W. Hilgemann, Massive endocytosis driven by lipidic forces originating in the outer plasmalemmal monolayer: a new approach to membrane recycling and lipid domains. J. Gen. Physiol. 137, 137–154 (2011)PubMedCrossRefGoogle Scholar
  9. M.I. Geli, H. Riezman, Endocytic internalization in yeast and animal cells: similar and different. J. Cell Sci. 111(Pt 8), 1031–1037 (1998)PubMedGoogle Scholar
  10. K. Hayashi, W. Shuai, Y. Sakamoto, H. Higashida, M. Yamagishi, S. Kupershmidt, Trafficking-competent KCNQ1 variably influences the function of HERG long QT alleles. Heart Rhythm 7, 973–980 (2010)PubMedCrossRefGoogle Scholar
  11. D.W. Hilgemann, M. Fine, Mechanistic analysis of massive endocytosis in relation to functionally defined surface membrane domains. J. Gen. Physiol. 137, 155–172 (2011)PubMedCrossRefGoogle Scholar
  12. D.W. Hilgemann, G.A. Langer, Transsarcolemmal calcium movements in arterially perfused rabbit right ventricle measured with extracellular calcium-sensitive dyes. Circ. Res. 54, 461–467 (1984)PubMedCrossRefGoogle Scholar
  13. D.W. Hilgemann, A. Yaradanakul, Y. Wang, D. Fuster, Molecular control of cardiac sodium homeostasis in health and disease. J. Cardiovasc. Electrophysiol. 17(Suppl 1), S47–S56 (2006)PubMedCrossRefGoogle Scholar
  14. T.J. Hund, P.J. Mohler, Ankyrin-based targeting pathway regulates human sinoatrial node automaticity. Channels (Austin) 2, 404–406 (2008)CrossRefGoogle Scholar
  15. A.I. Ivanov, Pharmacological inhibition of endocytic pathways: is it specific enough to be useful? Methods Mol. Biol. 440, 15–33 (2008)PubMedCrossRefGoogle Scholar
  16. S.H. Kim, T.A. Ryan, Synaptic vesicle recycling at CNS synapses without AP-2. J. Neurosci. 29, 3865–3874 (2009)PubMedCrossRefGoogle Scholar
  17. V. Lariccia, M. Fine, S. Magi, M.J. Lin, A. Yaradanakul, M.C. Llaguno, D.W. Hilgemann, Massive calcium-activated endocytosis without involvement of classical endocytic proteins. J. Gen. Physiol. 137, 111–132 (2011)PubMedCrossRefGoogle Scholar
  18. S.P. Lawrence, G.D. Holman, F. Koumanor, Translocation of the Na/H exchanger (NHE1) in cardiomyocyte responses to insulin and energy status signaling. Biochem. J. 432, 515–523 (2010)PubMedCrossRefGoogle Scholar
  19. S. Mayor, R.E. Pagano, Pathways of clathrin-independent endocytosis. Nat. Rev. Mol. Cell Biol. 8, 603–612 (2007)PubMedCrossRefGoogle Scholar
  20. G. Miesenbock, D.A. De Angelis, J.E. Rothman, Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394, 192–195 (1998)PubMedCrossRefGoogle Scholar
  21. O. Pongs, Ins and outs of cardiac voltage-gated potassium channels. Curr. Opin. Pharmacol. 9, 311–315 (2009)PubMedCrossRefGoogle Scholar
  22. J.E. Saffitz, J.G. Laing, K.A. Yamada, Connexin expression and turnover: implications for cardiac excitability. Circ. Res. 86, 723–728 (2000)PubMedCrossRefGoogle Scholar
  23. K. Sato, G.G. Ernstrom, S. Watanabe, R.M. Weimer, C.H. Chen, M. Sato, A. Siddiqui, E.M. Jorgensen, B.D. Grant, Differential requirements for clathrin in receptor-mediated endocytosis and maintenance of synaptic vesicle pools. Proc. Natl. Acad. Sci. U. S. A. 106, 1139–1144 (2009)PubMedCrossRefGoogle Scholar
  24. A. Zorzano, L. Sevilla, M. Camps, C. Becker, J. Meyer, H. Kammermeier, P. Munoz, A. Guma, X. Testar, M. Palacin, J. Blasi, Y. Fischer, Regulation of glucose transport, and glucose transporters expression and trafficking in the heart: studies in cardiac myocytes. Am. J. Cardiol. 80, 65A–76A (1997)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Donald W. Hilgemann
    • 1
    Email author
  • Mei-Jung Lin
    • 1
  • Michael Fine
    • 1
  • Gary Frazier
    • 1
  • Hao-Ran Wang
    • 1
  1. 1.Department of PhysiologyUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations