Abstract
In airway myocytes signal transduction via cytosolic calcium plays an important role. In relation with experimental results we review models of basic molecular and cellular mechanisms involved in the signal transduction from the myocyte stimulation to the activation of the contractile apparatus. We concentrate on mechanisms for encoding of input signals into Ca2+ signals and the mechanisms for their decoding. The mechanisms are arranged into a general scheme of cellular signaling, the so-called bow-tie architecture of signaling, in which calcium plays the role of a common media for cellular signals and links the encoding and decoding part. The encoding of calcium signals in airway myocytes is better known and is presented in more detail. In particular, we focus on three recent models taking into account the intracellular calcium handling and ion fluxes through the plasma membrane. The model of membrane conductances was originally proposed for predicting membrane depolarization and voltage-dependent Ca2+ influx triggered by initial cytosolic Ca2+ increase as observed on cholinergic stimulation. Cellular models of intracellular Ca2+ handling were developed to investigate the role of a mixed population of InsP3 receptor isoforms and the cellular environment in the occurrence of Ca2+ oscillations, and the respective role of the sarcoplasmic reticulum, mitochondria, and cytosolic Ca2+-binding proteins in cytosolic Ca2+ clearance. Modeling the mechanisms responsible for the decoding of calcium signals is developed in a lesser extent; however, the most recent theoretical studies are briefly presented in relation with the known experimental results.
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Roux, E., Molimard, M., Savineau, J. P., and Marthan, R. (1998) Muscarinic stimulation of airway smooth muscle cells. Gen. Pharmacol. 31, 349–356.
Prakash, Y. S., Kannan, M. S., Walseth, T. F., and Sieck, G. C. (1998) Role of cyclic ADP-ribose in the regulation of [Ca2+]i in porcine tracheal smooth muscle. Am. J. Physiol. 274, C1653-C1660.
Rodger, I. W. Voltage-dependent and receptor-operated calcium channels. In Airways Smooth Muscle: Biochemical Control of Contraction and Relaxation (Raeburn, D., Giembycz, M. A., ed.) Birkhäuser Verlag, Basel, 1994, pp. 155–168.
Marthan, R. (2004) Store-operated calcium entry and intracellular calcium release channels in airway smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 286, L907–8.
Roux, E. and Marhl, M. (2004) Role of sarcoplasmic reticulum and mitochondria in ca(2+) removal in airway myocytes. Biophys. J. 86, 2583–2595.
Somlyo, A. P. and Somlyo, A. V. (2003) Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol. Rev. 83, 1325–1358.
Bai, Y. and Sanderson, M. J. (2006) Modulation of the Ca2+ sensitivity of airway smooth muscle cells in murine lung slices. Am. J. Physiol. Lung Cell Mol. Physiol. 291(2), L208-L221.
Johnson, M. (1998) The beta-adrenoceptor. Am. J. Resp. Crit. Care Med. 158, S146-S153.
Janssen, L. J., Tazzeo, T., and Zuo, J. (2004) Enhanced myosin phosphatase and Ca(2+)-uptake mediate adrenergic relaxation of airway smooth muscle. Am. J. Resp. Cell Mol. Biol. 30, 548–554.
Murthy, K. S. (2006) Signaling for contraction and relaxation in smooth muscle of the gut. Annu. Rev. Physiol. 68, 345–374.
Schaafsma, D., Boterman, M., de Jong, A. M., Hovens, I., Penninks, J. M., Nelemans, S. A., Meurs, H., and Zaagsma, J. (2006) Differential Rho-kinase dependency of full and partial muscarinic receptor agonists in airway smooth muscle contraction. Br. J. Pharmacol. 147, 737–743.
Deng, J. T., Sutherland, C., Brautigan, D. L., Eto, M., and Walsh, M. P. (2002) Phosphorylation of the myosin phosphatase inhibitors, CPI-17 and PHI-1, by integrin-linked kinase. Biochem. J. 367, 517–524.
Huang, J., Mahavadi, S., Sriwai, W., Hu, W., and Murthy, K. S. (2006) Gi-coupled receptors mediate phosphorylation of CPI-17 and MLC20 via preferential activation of the PI3K/ILK pathway. Biochem. J. 396, 193–200.
Niiro, N. and Ikebe, M. (2001) Zipper-interacting protein kinase induces Ca(2+)-free smooth muscle contraction via myosin light chain phosphorylation. J. Biol. Chem. 276, 29567–29574.
Hirano, K., Derkach, D. N., Hirano, M., Nishimura, J., and Kanaide, H. (2003) Protein kinase network in the regulation of phosphorylation and dephosphorylation of smooth muscle myosin light chain. Mol. Cell Biochem. 248, 105–114.
Berridge, M. J., Lipp, P., and Bootman, M. D. (2000) The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell. Biol. 1, 11–21.
Csete, M. and Doyle, J. (2004) Bow ties, metabolism and disease. Trends Biotechnol. 22, 446–450.
Ma, H. W. and Zeng, A. P. (2003) The connectivity structure, giant strong component and centrality of metabolic networks. Bioinformatics 19, 1423–1430.
Schuster, S., Knoke, B., and Marhl, M. (2005) Differential regulation of proteins by bursting calcium oscillations—a theoretical study. Biosystems 81, 49–63.
Marhl, M., Perc, M., and Schuster, S. (2005) Selective regulation of cellular processes via protein cascades acting as band-pass filters for time-limited oscillations. FEBS Lett. 579, 5461–5465.
Howarth, P. H., Knox, A. J., Amrani, Y., Tliba, O., Panettieri, R. A., Jr., and Johnson, M. (2004) Synthetic responses in airway smooth muscle. J. Allergy Clin. Immunol. 114, S32-S50.
Bergner, A. and Sanderson, M. J. (2002) Acetylcholineinduced calcium signaling and contraction of airway smooth muscle cells in lung slices. J. Gen. Physiol. 119, 187–198.
Kajita, J. and Yamaguchi, H. (1993) Calcium mobilization by muscarinic cholinergic stimulation in bovine single airway smooth muscle. Am. J. Physiol. 264, L496-L503.
Perez, J. F. and Sanderson, M. J. (2005) The frequency of calcium oscillations induced by 5-HT, ACH, and KCl determine the contraction of smooth muscle cells of intrapulmonary bronchioles. J. Gen. Physiol. 125, 535–553.
Prakash, Y. S., Pabelick, C. M., Kannan, M. S., and Sieck, G. C. (2000) Spatial and temporal aspects of ACh-induced [Ca2+]i oscillations in porcine tracheal smooth muscle. Cell Calcium 27, 153–162.
Roux, E., Hyvelin, J. M., Savineau, J. P., and Marthan, R. (1998) Calcium signaling in airway smooth muscle cells is altered by in vitro exposure to the aldehyde acrolein. Am. J. Resp. Cell Mol. Biol. 19, 437–444.
Liu, X. and Farley, J. M. (1996) Frequency modulation of acetylcholine-induced Ca(++)-dependent Cl- current oscillations are mediated by 1, 4, 5-trisphosphate in tracheal myocytes. J. Pharmacol. Exp. Ther. 277, 796–804.
Hyvelin, J. M., Martin, C., Roux, E., Marthan, R., and Savineau, J. P. (2000) Human isolated bronchial smooth muscle contains functional ryanodine/caffeine-sensitive Ca-release channels. Am. J. Resp. Crit. Care Med. 162, 687–694.
Roux, E., Guibert, C., Savineau, J. P., and Marthan, R. (1997) [Ca2+]i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity. Br. J. Pharmacol. 120, 1294–1301.
Nuttle, L. C. and Farley, J. M. (1996) Frequency modulation of acetylcholine-induced oscillations in Ca++ and Ca(++)-activated Cl- current by cAMP in tracheal smooth muscle. J. Pharmacol. Exp. Ther. 277, 753–760.
Kannan, M. S., Prakash, Y. S., Brenner, T., Mickelson, J. R., and Sieck, G. C. (1997) Role of ryanodine receptor channels in Ca2+ oscillations of porcine tracheal smooth muscle. Am. J. Physiol. 272, L659-L664.
Guibert, C., Marthan, R., and Savineau, J. P. (1996) Angiotensin II-induced Ca(2+)-oscillations in vascular myocytes from the rat pulmonary artery. Am. J. Physiol. 270, L637-L642.
Drummond, R. M. and Tuft, R. A. (1999) Release of Ca2+ from the sarcoplasmic reticulum increases mitochondrial [Ca2+] in rat pulmonary artery smooth muscle cells. J. Physiol. 516, 139–147.
Pacher, P., Csordas, P., Schneider, T., and Hajnoczky, G. (2000) Quantification of calcium signal transmission from sarco-endoplasmic reticulum to the mitochondria, J. Physiol. 529, 553–564.
Vallot, O., Combettes, L., and Lompre, A. M. (2001) Functional coupling between the caffeine/ryanodine-sensitive Ca2+ store and mitochondria in rat aortic smooth muscle cells. Biochem. J. 357, 363–371.
Kamishima, T. and Quayle, J. M. (2002) Mitochondrial Ca2+ uptake is important over low [Ca2+]i range in arterial smooth muscle. Am. J. Physiol. Herat Circ. Physiol. 283, H2431-H2439.
Prakash, Y. S., Kannan, M. S., and Sieck, G. C. (1997) Regulation of intracellular calcium oscillations in porcine tracheal smooth muscle cells. Am. J. Physiol. 272, C966-C975.
Bergner, A. and Sanderson, M. J. (2002) ATP stimulates Ca2+ oscillations and contraction in airway smooth muscle cells of mouse lung slices. Am. J. Physiol. Lung Cell Mol. Physiol. 283, L1271-L1279.
Ouedraogo, N., Marthan, R., and Roux, E. (2003) The effects of propofol and etomidate on airway contractility in chronically hypoxic rats. Anesth. Analg. 96, 1035–1041.
Mounkaila, B., Marthan, R., and Roux, E. (2005) Biphasic effect of extracellular ATP on human and rat airways is due to multiple P2 purinoceptor activation. Resp. Res. 6, 143.
Roux, E., Noble, P. J., Noble, D., and Marhl, M. (2006) Modelling of calcium handling in airway myocytes. Prog. Biophys. Mol. Biol. 90, 64–87.
DiFrancesco, D. and Noble, D. (1985) A model of cardiac electrical activity incorporating ionic pumps and concentration changes. Phil. Trans. R. Soc. Lond. B Biol. Sci. 307, 353–398.
Vergara, C. and Latorre, R. (1983) Kinetics of Ca2+-activated K+ channels from rabbit muscle incorporated into planar bilayers. Evidence for a Ca2+ and Ba2+ blockade. J. Gen. Physiol. 82, 543–568.
Noble, D. (1999). Oxsoft Heart Program Manual. Oxsoft Ltd., Oxford, UK.
Janssen, L. J., Walters, D. K., and Wattie, J. (1997) Regulation of [Ca2+]i in canine airway smooth muscle by Ca(2+)-ATPase and Na+/Ca2+ exchange mechanisms. Am. J. Physiol. 273, L322-L330.
Blaustein, M. P., Golovina, V. A., Song, H., Choate, J., Lencesova, L., Robinson, S. W., and Wier, W. G. (2002) Organization of Ca2+ stores in vascular smooth muscle: functional implications. Novartis Found. Symp 246, 125–137; discussion 137–141, 221–227.
Roux, E., Tupin, A.-L., and Marthan, R. Effect of Na−K ATPase inhibition on calcium homeostasis in rat airway myocytes. 5th UK Calcium Signalling Conference, 2003, Liverpool, UK.
Ay, B., Prakash, Y. S., Pabelick, C. M., and Sieck, G. C. (2004) Store-operated Ca2+ entry in porcine airway smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 286, L909-L917.
Helli, P. B., Pertens, E., and Janssen, L. J. (2005) Cyclopiazonic acid activates a Ca2+-permeable, nonselective cation conductance in porcine and bovine tracheal smooth muscle. J. Appl. Physiol. 99, 1759–1768.
Haberichter, T., Roux, E., Marhl, M., and Mazat, J. (2002) The influence of different InsP(3) receptor isoforms on Ca(2+) signaling in tracheal smooth muscle cells. Bioelectrochemistry 57, 129.
Hyvelin, J. M., Roux, E., Prevost, M. C., Savineau, J. P., and Marthan, R. (2000) Cellular mechanisms of acrolein-induced alteration in calcium signaling in airway smooth musles. Toxicol. Appl. Pharmacol. 164, 176–183.
Li, Y. X. and Rinzel, J. (1994) Equations for Insp(3) receptor-mediated Ca2+ (I) oscillations derived from a detailed kinetic-model—a Hodgkin-Huxley like formalism. J. Theor. Biol. 166, 461–473.
Moraru, I. I., Kaftan, E. J., Ehrlich, B. E., and Watras, J. (1999) Regulation of type 1 inositol 1,4,5-trisphosphategated calcium channels by InsP(3) and calcium—simulation of single channel kinetics based on ligand binding and electrophysiological analysis. J. Gen. Physiol. 113, 837–849.
Hagar, R. E. and Ehrlich, B. E. (2000) Regulation of the type III InsP(3) receptor by InsP(3) and ATP. Biophys. J. 79, 271–278.
Marin, J., Encabo, A., Briones, A., Garcia-Cohen, E. C., and Alonso, M. J. (1999) Mechanisms involved in the cellular calcium homeostasis in vascular smooth muscle: calcium pumps. Life Sci. 64, 279–303.
Ogawa, Y., Kurebayashi, N., and Murayama, T. (2000) Putative roles of type 3 ryanodine receptor isoforms (RyR3). Trends Cardiovasc. Med. 10, 65–70.
Schuster, M., Marhl, M., and Hofer, T. (2002) Modelling of simple and complex calcium oscillations. From single-cell responses to intercellular signalling. Eur. J. Biochem. 269, 1333–1355.
Burdakov, D. and Verkhratsky, A. (2006) Biophysical re-equilibration of Ca2+ fluxes as a simple biologically plausible explanation for complex intracellular Ca2+ release patterns. FEBS Lett. 580, 463–468.
Montano, L. M. and Bazan-Perkins, B. (2005) Resting calcium influx in airway smooth muscle. Can. J. Physiol. Pharmacol. 83, 717–723.
Camello, C., Lomax, R., Petersen, O. H., and Tepikin, A. V. (2002) Calcium leak from intracellular stores—the enigma of calcium signalling. Cell Calcium 32, 355–361.
Lytton, J., Westlin, M., Burk, S. E., Shull, G. E., and Maclennan, D. H. (1992) Functional comparisons between isoforms of the sarcoplasmic or endoplasmic-reticulum family of calcium pumps. J. Biol. Chem. 267, 14483–14489.
Falcke, M. (2004) Reading the patterns in living cells—the of Ca2+ signaling. Adv. Phys. 53, 255–440.
Schuster, S., Marhl, M., and Hofer, T. (2002) Modelling of simple and complex calcium oscillations. From single-cell responses to intercellular signalling. Eur. J. Biochem. 269, 1333–1355.
Babcock, D. F. and Hille, B. (1998) Mitochondrial oversight of cellular Ca2+ signaling. Curr. Opin. Neurobiol. 8, 398–404.
Meyer, T. and Streyer, L. (1988) Molecular-model for receptor-stimulated calcium spiking. Proc. Natl. Acad. Sci. U.S.A. 85, 5051–5055.
Pozzan, T., Rizzuto, R., Volpe, P., and Meldolesi, J. (1994) Molecular and Cellular Physiology of Intracellular Calcium Stores. Physiol. Rev. 74, 595–636.
Jouaville, L. S., Ichas, F., Holmuhamedov, E. L., Camacho, P., and Lechleiter, J. D. (1995) Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature 377, 438–441.
Rizzuto, R., Pinton, P., Brini, M., Chiesa, A., Filippin, L., and Pozzan, T. (1999) Mitochondria as biosensors of calcium microdomains. Cell Calcium 26, 193–199.
Rutter, G. A. and Rizzuto, R. (2000) Regulation of mitochondrial metabolism by ER Ca2+ release: an intimate connection. Trends Biochem. Sci. 25, 215–221.
Petersen, O. H., Petersen, C. C. H., and Kasai, H. (1994) Calcium and hormone action. Annu. Rev. Physiol. 56, 297–319.
Hehl, S., Golard, A., and Hille, B. (1996) Involvement of mitochondria in intracellular calcium sequestration by rat gonadotropes. Cell Calcium 20, 515–524.
Babcock, D. F., Herrington, J., Goodwin, P. C., Park, Y. B., and Hille, B. (1997) Mitochondrial participation in the intracellular Ca2+ network. J. Cell Biol. 136, 833–844.
Simpson, P. B. and Russell, J. T. (1998) Role of mitochondrial Ca2+ regulation in neuronal and glial cell signalling. Brain Res. Rev. 26, 72–81.
Simpson, P. B. and Russell, J. T. (1998) Mitochondrial Ca2+ uptake and release influence metabotropic and ionotropic cytosolic Ca2+ responses in rat oligodendrocyte progenitors. J. Physiol. (Lond) 508, 413–426.
Rizzuto, R., Pinton, P., Carrington, W., Fay, F. S., Fogarty, K. E., Lifshitz, L. M., Tuft, R. A., and Pozzan, T. (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280, 1763–1766.
Drummond, R. M. and Fay, F. S. (1996) Mitochondria contribute to Ca2+ removal in smooth muscle cells. Pflugers Arch. 431, 473–482.
Szado, T., Kuo, K. H., Bernard-Helary, K., Poburko, D., Lee, C. H., Seow, C., Ruegg, U. T., and van Breemen, C. (2003) Agonist-induced mitochondrial Ca2+ transients in smooth muscle. FASEB J. 17, 28–37.
Marhl, M., Schuster, S., and Brumen, M. (1998) Mitochondria as an important factor in the maintenance of constant amplitudes of cytosolic calcium oscillations. Biophys. Chem. 2, 125–132.
Haberichter, T., Marhl, M., and Heinrich, R. (2001) Birhythmicity, trirhythmicity and chaos in bursting calcium oscillations. Biophys. Chem. 90, 17–30.
Grubelnik, V., Larsen, A. Z., Kummer, U., Olsen, L. F., and Marhl, M. (2001) Mitochondria regulate the amplitude of simple and complex calcium oscillations. Biophys. Chem. 94, 59–74.
Marhl, M., Schuster, S., Brumen, M., and Heinrich, R. (1998) Modelling oscillations of calcium and endoplasmic reticulum transmembrane potential; role of the signalling and buffering proteins and of the size of the Ca2+ sequestering ER subcompartments. Bioelectrochem. Bioenerg. 46, 79–90.
Marhl, M., Haberichter, T., Brumen, M., and Heinrich, R. (2000) Complex calcium oscillations and the role of mitochondria and cytosolic proteins. Biosystems 57, 75–86.
Ichas, F., Jouaville, L. S., Sidash, S. S., Mazat, J. P., and Holmuhamedov, E. L. (1994) Mitochondrial calcium spiking—a transduction mechanism-based on calcium-induced permeability transition involved in cell calcium signaling. FEBS Lett. 348, 211–215.
Ichas, F., Jouaville, L. S., and Mazat, J. P. (1997) Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89, 1145–1153.
Jouaville, L. S., Ichas, F., and Mazat, J. P. (1998) Modulation of cell calcium signals by mitochondria. Mol. Cell. Biochem. 184, 371–376.
Huser, J., Rechenmamcher, C. E., and Blatter, L. A. (1998) Imaging the permeability pore transition in single mitochondria. Biophys. J. 74, 2129–2137.
Falke, J. J., Drake, S. K., Hazard, A. L., and Peersen, O. B. (1994) Molecular tuning of ion binding to calcium signaling proteins. Q. Rev. Biophys. 27, 219–290.
Smith, G. D., Wagner, J., and Keizer, J. (1996) Validity of the rapid buffering approximation near a point source of calcium ions. Biophys. J. 70, 2527–2539.
Ideker, T. and Lauffenburger, D. (2003) Building with a scaffold: emerging strategies for high-to low-level cellular modeling. Trends Biotechnol. 21, 255–262.
Tyson, J. J., Chen, K. C., and Novak, B. (2003) Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr. Opin. Cell Biol. 15, 221–231.
Zaslaver, A., Mayo, A. E., Rosenberg, R., Bashkin, P., Sberro, H., Tsalyuk, M., Surette, M. G., and Alon, U. (2004) Just-in-time transcription program in metabokic pathways. Nat. Genet. 36, 486–491.
Schuster, S., Klipp, E., and Marhl, M. The predictive power of molecular network modelling—case studies of predictions with subsequent experimental verification. In Discovering Biomolecular Mechanisms with Computational Biology (Eisenhaber, F., ed.). Georgetown, Landes Bioscience, 2005, pp. 115–127.
Morel, J. L., Fritz, N., Lavie, J. L., and Mironneau, J. (2003) Crucial role of type 2 inositol 1,4,5-trisphosphate receptors for acetylcholine-induced Ca2+ oscillations in vascular myocytes. Arterioscler. Thromb. Vasc. Biol. 23, 1567–1575.
Hai, C. M. and Murphy, R. A. (1998) Regulation of short-ening velocity by cross-bridge phosphorylation in smooth muscle. Am. J. Physiol. Cell Physiol 255, C86-C94.
Rembold, C. M. and Murphy, R. A. (1990) Latch-bridge model in smooth-muscle-[Ca2+]i can quantitatively predict stress. Am. J. Physiol. 259, C251-C257.
Rembold, C. M., Wardle, R. L., Wingard, C. J., Batts, T. W., Etter, E. F., and Murphy, R. A. (2004) Cooperative attachment of cross bridges predicts regulation of smooth muscle force by myosin phosphorylation. Am. J. Physiol. Cell Physiol. 287, C594-C602.
Hai, C.-M. and Kim, H. R. (2005) An expanded latch-bridge model of protein kinase C-mediated smooth muscle contraction. J. Appl. Physiol. 98, 1356–1365.
Morgan, K. G. and Gangopadhyay, S. S. (2001) Invited review: cross-bridge regulation by thin filament-associated proteins. J. Appl. Physiol. 91, 953–962.
Hai, C. M. and Szeto, B. (1992) Agonist-induced myosin phosphorylation during isometric contraction and unloaded shortening in airway smooth muscle. Am. J. Physiol. 262, L53-L62.
Fajmut, A., Dobovisek, A., and Brumen, M. (2005) Mathematical modeling of the relation between myosin phosphorylation and stress development in smooth muscles. J. Chem. Inf. Model 45, 1610–1615.
Kato, S., Osa, T., and Ogasawara, T.. (1984) Kinetic-model for isometric contraction in smooth-muscle on the basis of myosin phosphorylation hypothesis. Biophys. J. 46, 35–44.
Fajmut, A., Brumen, M., and Schuster, S. (2005) Theoretical model of the interactions between Ca2+, calmodulin and myosin light chain kinase. FEBS Lett. 579, 4361–4366.
Noble, D. (2002) Modeling the heart—from genes to cells to the whole organ. Science 295, 1678–1682.
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Marhl, M., Noble, D. & Roux, E. Modeling of molecular and cellular mechanisms involved in Ca2+ signal encoding in airway myocytes. Cell Biochem Biophys 46, 285–302 (2006). https://doi.org/10.1385/CBB:46:3:285
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DOI: https://doi.org/10.1385/CBB:46:3:285