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Role of the Plasma Membrane Ca2+-ATPase Pump in the Regulation of Rhythm Generation by an Interstitial Cell of Cajal: A Computational Study

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Gastrointestinal motility is based on the rhythmic activity of interstitial cells of Cajal (ICCs). The ICC rhythm generation relies upon characteristic Ca2+-handling mechanisms that involve voltage-gated Ca2+ channels, pumps and exchangers located in the plasma membrane, endoplasmic reticulum (ER), and mitochondria. Mutations, overexpression, and genetic knockdowns of the plasma membrane calcium ATPase (PMCA) pumps have been shown to disrupt calcium signaling and to cause disorders in other cell systems. Using an ICC biophysical model, we investigated the effects of PMCA pump upregulation in ICC rhythm generation. We found that, depending on the PMCA maximum pumping rate, the ICC model generates voltage and Ca2+ oscillations with different characteristics or becomes silent. The model predicts the coexistence of activity regimes near a canonical set of the parameters. One of these regimes is a silent regime that would indicate gastric dysmotility.

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  1. 1.

    J. D. Huizinga and W. J. Lammers, “Gut peristalsis is governed by a multitude of cooperating mechanisms,” Am. J. Physiol. Gastrointest. Liver Physiol., 296, No. 1, G1–8 (2009).

  2. 2.

    D. F. van Helden, D. R. Laver, J. Holdsworth, and M. S. Imtiaz, “Generation and propagation of gastric slow waves,” Clin. Exp. Pharmacol. Physiol., 37, No. 4, 516–524 (2010).

  3. 3.

    K. M. Sanders, S. M. Ward, and S. D. Koh, “Interstitial cells: regulators of smooth muscle function,” Physiol. Rev., 94, No. 3, 859–907 (2014).

  4. 4.

    S. M. Ward, T. Ordog, S. D. Koh, et al., “Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria,” J. Physiol., 525, Pt. 2, 355–361 (2000).

  5. 5.

    P. J. Blair, P. L. Rhee, K. M. Sanders, and S. M. Ward, “The significance of interstitial cells in neurogastroenterology,” J. Neurogastroenterol. Motil., 20, No. 3, 294–317 (2014).

  6. 6.

    A. Corrias and M. L. Buist, “Quantitative cellular description of gastric slow wave activity,” Am. J. Physiol. Gastrointest. Liver Physiol., 294, No. 4, G989–995 (2008).

  7. 7.

    E. E. Strehler and M. Treiman, “Calcium pumps of plasma membrane and cell interior,” Curr. Mol. Med., 4, No. 3, 323–335 (2004).

  8. 8.

    J. I. E. Bruce, “Metabolic regulation of the PMCA: Role in cell death and survival,” Cell Calcium, 69, 28–36 (2018).

  9. 9.

    E. E. Strehler, “Plasma membrane calcium ATPases as novel candidates for therapeutic agent development,” J. Pharm. Pharm. Sci., 16, No. 2, 190–206 (2013).

  10. 10.

    J. B. Youm, N. Kim, J. Han, et al., “A mathematical model of pacemaker activity recorded from mouse small intestine,” Philos. Trans. A Math Phys. Eng. Sci., 364, No. 1842, 1135–1154 (2006).

  11. 11.

    R. A. Faville, A. J. Pullan, K. M. Sanders, and N. P. Smith, “A biophysically based mathematical model of unitary potential activity in interstitial cells of Cajal,” Biophys. J., 95, No. 1, 88–104 (2008).

  12. 12.

    R. Lees-Green, S. J. Gibbons, G. Farrugia, et al.,“Computational modeling of anoctamin 1 calciumactivated chloride channels as pacemaker channels in interstitial cells of Cajal,” Am. J. Physiol. Gastrointest. Liver Physiol., 306, No. 8, G711–727 (2014).

  13. 13.

    R. Lees-Green, P. Du, G. O’Grady, et al., “Biophysically based modeling of the interstitial cells of Cajal: current status and future perspectives,” Front. Physiol., 2, No. 29 (2011).

  14. 14.

    G. Magnus and J. Keizer, “Minimal model of beta-cell mitochondrial Ca2+ handling,” Am. J. Physiol., 273, No. 2, Pt. 1, C717–733 (1997).

  15. 15.

    C. P. Fall and J. E. Keizer, “Mitochondrial modulation of intracellular Ca(2+) signaling,” J. Theor. Biol., 210, No. 2, 151–165 (2001).

  16. 16.

    S. Torihashi, T. Fujimoto, C. Trost, and S. Nakayama, “Calcium oscillation linked to pacemaking of interstitial cells of Cajal: requirement of calcium influx and localization of TRP4 in caveolae,” J. Biol. Chem., 277, No. 21, 19191–19197 (2002).

  17. 17.

    G. D. Hirst and F. R. Edwards, “Generation of slow waves in the antral region of guinea-pig stomach – a stochastic process,” J. Physiol., 535, Pt 1, 165–180 (2001).

  18. 18.

    M. Brini, T. Cali, D. Ottolini, and E. Carafoli, “The plasma membrane calcium pump in health and disease,” FEBS J., 280, No. 21, 5385–5397 (2013).

  19. 19.

    R. Gros, T. Afroze, X. M. You, et al., “Plasma membrane calcium ATPase overexpression in arterial smooth muscle increases vasomotor responsiveness and blood pressure,” Circ. Res., 93, No. 7, 614–621 (2003).

  20. 20.

    W. J. Cho and E. E. Daniel, “Proteins of interstitial cells of Cajal and intestinal smooth muscle, colocalized with caveolin-1,” Am. J. Physiol. Gastrointest. Liver Physiol., 288, No. 3, G571–585 (2005).

  21. 21.

    N. E. Diamant and A. Bortoff, “Nature of the intestinal slow-wave frequency gradient”. Am J. Physiol., 216, No. 2, 301–307 (1969).

  22. 22.

    S. M. Korogod, G. S. Cymbalyuk, I. A. Makedonsky, and I. B. Kulagina, “Hypoxic depression of pacemaker activity of interstitial cells of Cajal: A threat of gastrointestinal dysmotility and necrosis. A simulation study,” Neurophysiology, 50, No. 2, 76–82 (2018).

  23. 23.

    V. H. Oliveira, K. S. Nascimento, M. M. Freire, et al., “Mechanism of modulation of the plasma membrane Ca(2+)-ATPase by arachidonic acid,” Prostaglandins Other Lipid Mediat., 87, Nos. 1–4, 47–53 (2008).

  24. 24.

    M. F. Pignataro, M. M. Dodes-Traian, F. L. Gonzalez-Flecha, et al., “Modulation of plasma membrane Ca2+- ATPase by neutral phospholipids: effect of the micellevesicle transition and the bilayer thickness,” J. Biol. Chem., 290, No. 10, 6179–6190 (2015).

  25. 25.

    T. Sammour, A. Mittal, B. P. Loveday, et al., “Systematic review of oxidative stress associated with pneumoperitoneum,” Br. J. Surg., 96, No. 8, 836–850 (2009).

  26. 26.

    S. Hatipoglu, S. Akbulut, F. Hatipoglu, and R. Abdullayev, “Effect of laparoscopic abdominal surgery on splanchnic circulation: historical developments,” World J. Gastroenterol., 20, No. 48, 18165–18176 (2014).

  27. 27.

    Y. Guan, R. T. Worrell, T. A. Pritts, and M. H. Montrose, “Intestinal ischemia-reperfusion injury: reversible and irreversible damage imaged in vivo,” Am. J. Physiol. Gastrointest. Liver Physiol., 297, No. 1, G187–196 (2009).

  28. 28.

    N. Shimojima, T. Nakaki, Y. Morikawa, et al., “Interstitial cells of Cajal in dysmotility in intestinal ischemia and reperfusion injury in rats,” J. Surg. Res., 135, No. 2, 255–261 (2006).

  29. 29.

    K. Bielefeldt and J. L. Conklin, “Intestinal motility during hypoxia and reoxygenation in vitro,” Dig. Dis. Sci., 42, No. 5, 878–884 (1997).

  30. 30.

    S. Yilmaz, C. Polat, A. Kahraman, et al., “The comparison of the oxidative stress effects of different gases and intra-abdominal pressures in an experimental rat model,” J Laparoendosc. Adv. Surg. Tech. A, 14, No. 3, 165–168 (2004).

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Correspondence to G. S. Cymbalyuk.

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Ellingson, P.J., Korogod, S.M., Kahl, T.M. et al. Role of the Plasma Membrane Ca2+-ATPase Pump in the Regulation of Rhythm Generation by an Interstitial Cell of Cajal: A Computational Study. Neurophysiology (2020).

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  • interstitial cells of Cajal
  • calcium signaling
  • plasma membrane Ca2+-ATPase (PMCA) pump
  • gastrointestinal motility
  • multistability
  • coexistence.