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A Computational Model of the Ionic Currents, Ca2+ Dynamics and Action Potentials Underlying Contraction of Isolated Uterine Smooth Muscle

By Wing-Chiu Tong, Cecilia Y. Choi, Sanjay Karche, Arun V. Holden, Henggui Zhang and Michael J. Taggart

Abstract

Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP) of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C) coupling of uterine smooth muscle cells (USMC). Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs: currents (L- and T-type), current, an hyperpolarization-activated current, three voltage-gated currents, two -activated current, -activated current, non-specific cation current, - exchanger, - pump and background current. The magnitudes and kinetics of each current system in a spindle shaped single cell with a specified surface area∶volume ratio is described by differential equations, in terms of maximal conductances, electrochemical gradient, voltage-dependent activation/inactivation gating variables and temporal changes in intracellular computed from known fluxes. These quantifications are validated by the reconstruction of the individual experimental ionic currents obtained under voltage-clamp. Phasic contraction is modeled in relation to the time constant of changing . This integrated model is validated by its reconstruction of the different USMC AP configurations (spikes, plateau and bursts of spikes), the change from bursting to plateau type AP produced by estradiol and of simultaneous experimental recordings of spontaneous AP, and phasic force. In summary, our advanced mathematical model provides a powerful tool to investigate the physiological ionic mechanisms underlying the genesis of uterine electrical E-C coupling of labor and parturition. This will furnish the evolution of descriptive and predictive quantitative models of myometrial electrogenesis at the whole cell and tissue levels

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3084699
Provided by: PubMed Central

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Citations

  1. (1989). [Na] and [K] dependence of the Na/K pump current-voltage relationship in guinea pig ventricular myocytes.
  2. (1994). A
  3. (1982). A binding-site model for calcium channel inactivation that depends on calcium entry.
  4. (2004). A mathematical treatment of integrated Ca dynamics within the ventricular myocyte.
  5. (1996). Activation of calcium-dependent chloride channels in rat parotid acinar cells.
  6. (1984). Activity of circular muscle of rat uterus at different times in pregnancy.
  7. (1997). Agonist mobilization of sarcoplasmic reticular calcium in smooth muscle: Functional coupling to the plasmalemmal Na +/Ca 2+ exchanger?
  8. (2001). Allosteric regulation of Na/Ca exchange current by cytosolic Ca in intact cardiac myocytes.
  9. (2006). Alterations in uterine sodium pump abundance may contribute to the onset and progression of term and preterm labor in mice.
  10. (2004). Analysis of maxi-K alpha subunit splice variants in human myometrium.
  11. (1996). Analysis of the time course of calciumactivated chloride ‘tail’ currents in rabbit portal vein smooth muscle cells.
  12. (2009). Are animal models relevant to key aspects of human parturition?
  13. (2009). Bemis A
  14. (2000). BK(Ca) channel activation by membrane-associated cGMP kinase may contribute to uterine quiescence in pregnancy.
  15. (1996). Ca 2+ sparks and Ca 2+ waves activate different Ca 2+-dependent ion channels in single myocytes from rat portal vein.
  16. (1992). Ca 2+-activated K + channels in pregnant rat myometrium: modulation by a beta-adrenergic agent.
  17. (1999). Calcium antagonistic properties of the cyclooxygenase-2 inhibitor nimesulide in human myometrial myocytes.
  18. (1993). Calcium-activated K + channels as modulators of human myometrial contractile activity.
  19. (1998). Carboxyeosin decreases the rate of decay of the [Ca 2+]i, transient in uterine smooth muscle cells isolated from pregnant rats.
  20. (2007). Cellular ionic mechanisms controlling uterine smooth muscle contraction: effects of gestational state.
  21. (2003). Changes in the isoforms of the sodium pump in the placenta and myometrium of women in labor.
  22. (1995). Changes in transcripts encoding calcium channel subunits of rat myometrium during pregnancy.
  23. (1970). Characteristics of electrogenic sodium pumping in rat myometrium.
  24. (1993). Characterization of largeconductance, calcium-activated potassium channels from human myometrium.
  25. (2007). Characterization of the molecular and electrophysiological properties of the Ttype calcium channel in human myometrium.
  26. (2009). Cloning and characterization of a calcium-activated chloride channel in rat uterus.
  27. (1994). Cloning of the NCX2 isoform of the plasma membrane Na +-Ca 2+ exchanger.
  28. (1998). Contribution of calcium-sensitive potassium channels to NS1619-induced relaxation in human pregnant myometrium.
  29. (1983). Dependence of cellular potential on ionic concentrations. data supporting a modification of the constant field equation.
  30. (1996). Depolarization-evoked increases in cytosolic calcium concentration in isolated smooth muscle cells of rat portal vein.
  31. (2005). Differential expression of L- and T-type calcium channels between, longitudinal and circular muscles of the rat myometrium during pregnancy.
  32. (1998). Differential inhibition of Na +/Ca 2+ exchanger isoforms by divalent cations and isothiourea derivative.
  33. (2010). Distribution, expression and functional effects of small conductance Caactivated potassium (SK) channels in rat myometrium.
  34. (2003). Downregulation of the alpha- and beta-subunits of the calcium-activated potassium channel in human myometrium with parturition.
  35. (1979). Effect of isoproterenol on the isolated pregnant rat myometrium.
  36. (1971). Effects of changing the ionic environment on passive and active membrane properties of pregnant rat uterus.
  37. (1995). Effects of estrogens on Ca channels in myometrial cells isolated from pregnant rats.
  38. (1963). Effects of ions and drugs on cell membrane activity and tension in the postpartum rat myometrium.
  39. (2002). Effects of mibefradil on uterine contractility.
  40. (1993). Effects of pH and inorganic phosphate on force production in alpha-toxin-permeabilized isolated rat uterine smooth muscle.
  41. (1988). Effects of tetraethylammonium and 4-aminopyridine on the plateau potential of circular myometrium from the pregnant rat.
  42. (2004). Electrophysiological characterization and functional importance of calcium-activated chloride channel in rat uterine myocytes.
  43. (1986). Electrophysiological characterization of single pregnant rat myometrial cells in short-term primary culture.
  44. (1994). Electrophysiology of the human myometrium. In:
  45. (2008). Epidemiology and causes of preterm birth.
  46. (1999). Estradiol inhibits Ca 2+ and K + channels in smooth muscle cells from pregnant rat myometrium.
  47. (1969). Evidence for an electrogenic sodium pump in smooth muscle.
  48. (2001). Excitability in uterine smooth muscle.
  49. (1989). Fast Na + and slow Ca 2+ channels in single uterine muscle cells from pregnant rats.
  50. (1992). Fast Na + channels and slow Ca 2+ current in smooth muscle from pregnant rat uterus.
  51. (1991). Fujiwara A
  52. (2005). Gating and ionic currents reveal how the BK(Ca) channel’s Ca 2+ sensitivity is enhanced by its beta1 subunit.
  53. (1991). Gestational change in Na + and Ca 2+ channel current densities, in rat myometrial smooth muscle cells.
  54. (1999). Hormonal control of protein expression and mRNA levels of the MaxiK channel alpha subunit in myometrium.
  55. (1999). Hyperpolarization and slowing of the rate of contraction in human uterus in pregnancy by prostaglandins E2 and F2a: Involvement of the Na + pump.
  56. (1995). Identification of a hyperpolarization-activated inward current in uterine smooth muscle cells during pregnancy.
  57. (2004). Identification of a nonselective cation channel current in myometrial cells isolated from pregnant rats.
  58. (2007). In situ calcium signaling. no calcium sparks detected in rat myometrium.
  59. (1986). Inactivation of calcium channel current in rat uterine smooth muscle: evidence for calcium- and voltagemediated mechanisms.
  60. (1995). Inhibition of L-type calcium current by genistein, a tyrosine kinase inhibitor, in pregnant rat myometrial cells.
  61. (2007). Mathematical model of excitation-contraction in a uterine smooth muscle cell.
  62. (2009). Mathematical modeling of electrical activity of uterine muscle cells.
  63. (2006). Mechanism of the inhibition of Ca 2+-activated Cl 2 currents by phosphorylation in pulmonary arterial smooth muscle cells.
  64. (2010). Mobasheri A
  65. (2001). Modulation of potassium current characteristics in human myometrial smooth muscle by 17beta-estradiol and progesterone.
  66. (2007). Myometrial expression of small conductance Ca 2+-activated K + channels depresses phasic uterine contraction.
  67. (1981). Na-Ca exchange in rat myometrium membrane vesicles highly enriched in plasma membranes.
  68. (1995). Noma A
  69. (2006). Outcomes of labours augmented with oxytocin.
  70. (2008). Patterns of electrical propagation in the intact pregnant guinea pig uterus.
  71. (1999). Physiological significance of hyperpolarization-activated inward currents (ih) in smooth muscle cells from the circular layers of pregnant rat myometrium.
  72. (2007). Physiology and electrical activity of uterine contractions.
  73. (2001). Potassium channels in the human myometrium.
  74. (1991). Potassium currents in freshly dispersed myometrial cells.
  75. (1998). Potassium currents in freshly dissociated uterine myocytes from nonpregnant and latepregnant rats.
  76. (2000). Pregnancy switches adrenergic signal transduction in rat and human uterine myocytes as probed by BKCa channel activity.
  77. (1993). Properties of largeconductance K + channels in human myometrium during pregnancy and labour.
  78. (1998). Properties of voltage-activated [Ca 2+]i transients in, single smooth muscle cells isolated from pregnant rat uterus.
  79. (1994). Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells.
  80. (2000). Regulation of the Ca 2+-sensitive domains of the maxi-K channel in the mouse myometrium during gestation.
  81. (2007). Regulation of the uterine contractile apparatus and cytoskeleton.
  82. (1959). Relationships between contraction and membrane electrical activity in the isolated uterus of the pregnant rat.
  83. (2009). Role of T-type Ca channels in the spontaneous phasic contraction of pregnant rat uterine smooth muscle.
  84. (2002). Simulating, analyzing, and animating dynamical systems: a guide to XPPAUT for researchers and students.
  85. (1998). Simultaneous measurements of electrical activity, intracellular calcium and contraction in smooth muscle.
  86. (1987). Single channel Cl 2 and K + currents from cells of uterus not treated with enzymes.
  87. (2003). Slow inactivation of the Cav3.1 isotype of T-type calcium channels.
  88. (1997). Sodium and calcium inward currents in freshly dissociated smooth myocytes of rat uterus.
  89. (1999). Sodium-potassium pump current in smooth muscle cells from mesenteric resistance arteries of the guinea-pig.
  90. (1990). Some electrical properties of human pregnant myometrium.
  91. (1999). State-dependent inactivation of the alpha1G T-type calcium channel.
  92. (2006). Steroid hormone regulation of Clca3 expression in the murine uterus.
  93. (2006). Structural determinants for functional coupling between the beta and alpha subunits in the Ca 2+-activated K + (BK) channel.
  94. (1988). Studies of the sodium-calcium exchanger in bull-frog atrial myocytes.
  95. (1993). T-type and L-type calcium currents in freshly dispersed human uterine smooth muscle cells.
  96. (2009). Temporal and spatial variations in spontaneous Ca events and mechanical activity in pregnant rat myometrium.
  97. (1992). The activity of Na +/ K +-ATPase and abundance of its mRNA are regulated in rat myometrium during pregnancy.
  98. (1987). The calcium channel current of pregnant rat single myometrial cells, in short-term primary culture.
  99. (2011). The contribution of Kv7 channels to pregnant mouse and human myometrial contractility.
  100. (1994). The influence of 17 betaoestradiol on K + currents in smooth muscle cells isolated from immature rat uterus.
  101. (1988). The Na +/ Ca 2+ antiporter in aortic smooth muscle cells.
  102. (2010). The pregnancy dependent expression profile of the genomic complement of K channels in human myometrial smooth muscle and vasculature.
  103. (1999). The role of the sarcoplasmic reticulum as a Ca 2+ sink in rat uterine smooth muscle cells.
  104. (2007). The role of voltage-gated potassium channels in the regulation of mouse uterine contractility. Reprod Biol Endocrinol 5: 41. Modeling Uterine
  105. (2007). Three types of muscles express three sodium-calcium exchanger isoforms.
  106. (1997). Tissue specificity and alternative splicing of the Na +/Ca 2+ exchanger isoforms NCX1, NCX2, and NCX3 in rat.
  107. (2002). Tissue-specific regulation of Ca 2+ channel protein expression by sex hormones.
  108. (2007). Towards understanding the myometrial physiome: approaches for the construction of a virtual physiological uterus.
  109. (1956). Transmembrane potentials and contractility in the pregnant rat uterus.
  110. (1999). Voltage-gated K + currents in freshly isolated myocytes of, the pregnant human myometrium.