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Regulation of Cellular Molecular Signaling by Light (Invited Paper)

By Pan Cheng, Yujie Zhu, and Hao He
Progress In Electromagnetics Research, Vol. 154, 209-225, 2015


Laser technology has been promoting various microscopy methods and thus making great progresses in life science. Further than contribution to ``seeing is believing'', lasers have also demonstrated their capacity of manipulating cells and even molecular signaling. Specifically, with advances of lasers and combination with other techniques, recent reports show that cell calcium ion, a universal intra- and inter-cellular messenger, can be modulated by lasers at different levels of biological organization from organelle to tissue. It is very encouraging that laser irradiation can activate or control plenty of corresponding cell processes and functions by regulating cell calcium signaling pathways, with promising potential in both scientific research and clinical application. In this paper, optical techniques for regulation of cell calcium signaling are specifically reviewed. Most methods need exogenouschemicals or genetic materials to convert incident photon into stimulation that cells can response with specific molecular dynamics. The only all-optical approach is achieved by nonlinear excitation with femtosecond laser, despite lack of specificity and controllability, providing possibility of a totally noninvasive method without any biochemical materials and thus further potential clinical application in human beings. The developments and techniques of those methods are introduced and explained, with analysis on their properties and current challenges. Potential applications and prospective development are also discussed. Researchers on biophotonics and related biological fields can benefit from this review. It also provides a systematic reference to doctors and researchers who are working on practical application of those methods.


Pan Cheng, Yujie Zhu, and Hao He, "Regulation of Cellular Molecular Signaling by Light (Invited Paper)," Progress In Electromagnetics Research, Vol. 154, 209-225, 2015.


    1. Ashkin, A. and J. M. Dziedzic, "Optical trapping and manipulation of viruses and bacteria," Science, Vol. 235, No. 4795, 1517-1520, Mar. 1987.

    2. Tirlapur, U. K. and K. König, "Cell biology: Targeted transfection by femtosecond laser," Nature, Vol. 418, No. 6895, 290-291, Jul. 2002.

    3. Yanik, M. F., H. Cinar, H. N. Cinar, A. D. Chisholm, Y. Jin, and A. Ben-Yakar, "Neurosurgery: Functional regeneration after laser axotomy," Nature, Vol. 432, No. 7019, 822-822, Dec. 2004.

    4. Adams, S. R., J. P. Y. Kao, G. Grynkiewicz, A. Minta, and R. Y. Tsien, "Biologically useful chelators that release Ca2+ upon illumination," J. Am. Chem. Soc., Vol. 110, No. 10, 3212-3220, May 1988.

    5. Boyden, E. S., F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, "Millisecond-timescale, genetically targeted optical control of neural activity," Nat. Neurosci., Vol. 8, No. 9, 1263-1268, Sep. 2005.

    6. Smith, N. I., K. Fujita, T. Kaneko, K. Katoh, O. Nakamura, S. Kawata, and T. Takamatsu, "Generation of calcium waves in living cells by pulsed-laser-induced photodisruption," Applied Physics Letters, Vol. 79, No. 8, 1208-1210, Aug. 2001.

    7. Berridge, M. J., M. D. Bootman, and H. L. Roderick, "Calcium signalling: Dynamics, homeostasis and remodelling," Nat. Rev. Mol. Cell Biol., Vol. 4, No. 7, 517-529, Jul. 2003.

    8. Berridge, M. J., M. D. Bootman, and P. Lipp, "Calcium - A life and death signal," Nature, Vol. 395, No. 6703, 645-648, Oct. 1998.

    9. Dolmetsch, R. E., R. S. Lewis, C. C. Goodnow, and J. I. Healy, "Differential activation of transcription factors induced by Ca2+ response amplitude and duration," Nature, Vol. 386, No. 6627, 855-858, Apr. 1997.

    10. Paemeleire, K., P. E. M. Martin, S. L. Coleman, K. E. Fogarty, W. A. Carrington, L. Leybaert, R. A. Tuft, W. H. Evans, and M. J. Sanderson, "Intercellular calcium waves in Hela cells expressing GFP-labeled connexin 43, 32, or 26," Mol. Biol. Cell, Vol. 11, No. 5, 1815-1827, May 2000.

    11. Fauquier, T., N. C. Guérineau, R. A. McKinney, K. Bauer, and P. Mollard, "Folliculostellate cell network: A route for long-distance communication in the anterior pituitary," Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 15, 8891-8896, Jul. 2001.

    12. Jacob, R., J. E. Merritt, T. J. Hallam, and T. J. Rink, "Repetitive spikes in cytoplasmic calcium evoked by histamine in human endothelial cells," Nature, Vol. 335, No. 6185, 40-45, 1988.

    13. Dolmetsch, R. E., K. Xu, and R. S. Lewis, "Calcium oscillations increase the efficiency and specificity of gene expression," Nature, Vol. 392, No. 6679, 933-936, Apr. 1998.

    14. Carafoli, E., "Special issue: Calcium signaling and disease," Biochemical and Biophysical Research Communications, Vol. 322, No. 4, 1097, Oct. 2004.

    15. Sanderson, M. J., A. C. Charles, S. Boitano, and E. R. Dirksen, "Mechanisms and function of intercellular calcium signaling," Molecular and Cellular Endocrinology, Vol. 98, No. 2, 173-187, Jan. 1994.

    16. L. Spyracopoulos, M., X. Li, S. K. Sia, S. M. Gagn, M. Chandra, R. J. Solaro, and B. D. Sykes, "Calcium-induced structural transition in the regulatory domain of human cardiac troponin C," Biochemistry, Vol. 36, No. 40, 12138-12146, Oct. 1997.

    17. Chin, D. and A. R. Means, "Calmodulin: A prototypical calcium sensor," Trends in Cell Biology, Vol. 10, No. 8, 322-328, Aug. 2000.

    18. Brose, N., et al., "Synaptotagmin: A calcium sensor on the synaptic vesicle surface," Science, Vol. 256, No. 5059, 1021, May 1992.

    19. Szabadkai, G. and M. R. Duchen, "Mitochondria: The hub of cellular Ca2+ signaling," Physiology, Vol. 23, No. 2, 84-94, Apr. 2008.

    20. Csordás, G. and G. Hajnóczky, "Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria," Cell Calcium., Vol. 29, No. 4, 249-262, Apr. 2001.

    21. Camello-Almaraz, C., P. J. Gomez-Pinilla, M. J. Pozo, and P. J. Camello, "Mitochondrial reactive oxygen species and Ca2+ signaling," AJP: Cell Physiology, Vol. 291, No. 5, C1082-C1088, Nov. 2006.

    22. Yan, Y., J. Liu, C. Wei, K. Li, W. Xie, Y. Wang, and H. Cheng, "Bidirectional regulation of Ca2+ sparks by mitochondria-derived reactive oxygen species in cardiac myocytes," Cardiovasc. Res., Vol. 77, No. 2, 432-441, Jan. 2008.

    23. Papa, S. and V. P. Skulachev, "Reactive oxygen species, mitochondria, apoptosis and aging," Mol. Cell Biochem., Vol. 174, No. 1-2, 305-319, Sep. 1997.

    24. Miller, D. L. and J. I. Korenbrot, "Kinetics of light-dependent Ca fluxes across the plasma membrane of rod outer segments. A dynamic model of the regulation of the cytoplasmic Ca concentration," J. Gen. Physiol., Vol. 90, No. 3, 397-425, Sep. 1987.

    25. Yau, K.-W. and K. Nakatani, "Light-induced reduction of cytoplasmic free calcium in retinal rod outer segment," Nature, Vol. 313, No. 6003, 579-582, Feb. 1985.

    26. Neuhaus, G., C. Bowler, R. Kern, and N.-H. Chua, "Calcium/calmodulin-dependent and -independent phytochrome signal transduction pathways," Cell, Vol. 73, No. 5, 937-952, Jun. 1993.

    27. Sineshchekov, O. A. and E. G. Govorunova, "Rhodopsin-mediated photosensing in green flagellated algae," Trends in Plant Science, Vol. 4, No. 2, 58-63, Feb. 1999.

    28. Saranak, J. and K. W. Foster, "Photoreceptor for curling behavior in peranema trichophorum and evolution of eukaryotic rhodopsins," Eukaryotic Cell, Vol. 4, No. 10, 1605-1612, Oct. 2005.

    29. Specht, K. G. and M. A. J. Rodgers, "Plasma membrane depolarization and calcium influx during cell injury by photodynamic action," Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1070, No. 1, 60-68, Nov. 1991.

    30. Tarr, M. and D. P. Valenzeno, "Modification of cardiac ionic currents by photosensitizer-generated reactive oxygen," Journal of Molecular and Cellular Cardiology, Vol. 23, No. 5, 639-649, May 1991.

    31. Yonuschot, G., "Early increase in intracellular calcium during photodynamic permeabilization," Free Radical Biology and Medicine, Vol. 11, No. 3, 307-317, 1991.

    32. Penning, L. C., M. H. Rasch, E. Ben-Hur, T. M. A. R. Dubbelman, A. C. Havelaar, J. Van der Zee, and J. Van Steveninck, "A role for the transient increase of cytoplasmic free calcium in cell rescue after photodynamic treatment," Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1107, No. 2, 255-260, Jun. 1992.

    33. Ben-Hurt, E. and T. M. A. R. Dubbelman, "Cytoplasmic free calcium changes as a trigger mechanism in the response of cells to photosensitization," Photochemistry and Photobiology, Vol. 58, No. 6, 890-894, Dec. 1993.

    34. Gederaas, O. A., K. Thorstensen, and I. Romslo, "The effect of brief illumination on intracellular free calcium concentration in cells with 5-aminolevulinic acid-induced protoporphyrin IX synthesis," Scandinavian Journal of Clinical and Laboratory Investigation, Vol. 56, No. 7, 583-589, Jan. 1996.

    35. Rück, A., K. Heckelsmiller, R. Kaufmann, N. Grossman, E. Haseroth, and N. Akgün, "Light-induced apoptosis involves a defined sequence of cytoplasmic and nuclear calcium release in AlPcS4-photosensitized rat bladder RR 1022 epithelial cells," Photochemistry and Photobiology, Vol. 72, No. 2, 210-216, Aug. 2000.

    36. Granville, D. J., D. O. Ruehlmann, J. C. Choy, B. A. Cassidy, D. W. C. Hunt, C. van Breemen, and B. M. McManus, "Bcl-2 increases emptying of endoplasmic reticulum Ca2+ stores during photodynamic therapy-induced apoptosis," Cell Calcium, Vol. 30, No. 5, 343-350, Nov. 2001.

    37. Tarr, M., A. Frolov, and D. P. Valenzeno, "Photosensitization-induced calcium overload in cardiac cells: Direct link to membrane permeabilization and calcium influx," Photochemistry and Photobiology, Vol. 73, No. 4, 418-424, Apr. 2001.

    38. Zhou, Z., H. Yang, and Z. Zhang, "Role of calcium in phototoxicity of 2-butylamino-2-demethoxy-hypocrellin a to human gastric cancer MGC-803 cells," Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1593, No. 2-3, 191-200, Feb. 2003.

    39. Ding, X., Q. Xu, F. Liu, P. Zhou, Y. Gu, J. Zeng, J. An, W. Dai, and X. Li, "Hematoporphyrin monomethyl ether photodynamic damage on HeLa cells by means of reactive oxygen species production and cytosolic free calcium concentration elevation," Cancer Letters, Vol. 216, No. 1, 43-54, Dec. 2004.

    40. Ito, A., S. Hosokawa, S. Hakomori, S. Miyoshi, K. Soejima, and T. Arai, "The mechanism of PDT-induced electrical blockade: the measurement of intracellular Ca2+ concentration changes in cardiac myocytes," Biomedical Optics (BiOS) 2008. International Society for Optics and Photonics, Vol. 6854, 68540M-68540M-5, 2008.

    41. Qiao, X., C. Huang, Y. Ying, X. Yang, Y. Liu, and Q. Tian, "Involvement of reactive oxygen species and calcium in photo-induced membrane damage in HeLa cells by a bis-methanophosphonate fullerene," Journal of Photochemistry and Photobiology B: Biology, Vol. 98, No. 3, 193-198, Mar. 2010.

    42. Robertson, C. A., D. H. Evans, and H. Abrahamse, "Photodynamic therapy (PDT): A short review on cellular mechanisms and cancer research applications for PDT," Journal of Photochemistry and Photobiology B: Biology, Vol. 96, No. 1, 1-8, Jul. 2009.

    43. Cui, Z. J., Y. Habara, D. Y. Wang, and T. Kanno, "A novel aspect of photodynamic action: Induction of recurrent spikes in cytosolic calcium concentration," Photochemistry and Photobiology, Vol. 65, No. 2, 382-386, Feb. 1997.

    44. Lipp, P. and E. Niggli, "Submicroscopic calcium signals as fundamental events of excitation–contraction coupling in guinea-pig cardiac myocytes," The Journal of Physiology, Vol. 492, No. 1, 31-38, Apr. 1996.

    45. Kasai, H., "Comparative biology of Ca2+-dependent exocytosis: Implications of kinetic diversity for secretory function," Trends in Neurosciences, Vol. 22, No. 2, 88-93, Feb. 1999.

    46. Bollmann, J. H., B. Sakmann, and J. G. Borst, "Calcium sensitivity of glutamate release in a calyx-type terminal," Science, Vol. 289, No. 5481, 953-957, Aug. 2000.

    47. Lohmann, C., A. Finski, and T. Bonhoeffer, "Local calcium transients regulate the spontaneous motility of dendritic filopodia," Nat. Neurosci., Vol. 8, No. 3, 305-312, Mar. 2005.

    48. Adams, S. R. and R. Y. Tsien, "Controlling cell chemistry with caged compounds," Annual Review of Physiology, Vol. 55, No. 1, 755-784, 1993.

    49. Ellis-Davies, G. C. R., "Caged compounds: Photorelease technology for control of cellular chemistry and physiology," Nat. Meth., Vol. 4, No. 8, 619-628, Aug. 2007.

    50. Lipp, P. and E. Niggli, "Fundamental calcium release events revealed by two-photon excitation photolysis of caged calcium in guinea-pig cardiac myocytes," The Journal of Physiology, Vol. 508, No. 3, 801-809, May 1998.

    51. Echevarría, W., M. F. Leite, M. T. Guerra, W. R. Zipfel, and M. H. Nathanson, "Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum," Nat. Cell Biol., Vol. 5, No. 5, 440-446, May 2003.

    52. Chen, Y., J. Mancuso, Z. Zhao, X. Li, J. Cheng, G. Roman, and S. T. C. Wong, "Vasodilation by in vivo activation of astrocyte endfeet via two-photon calcium uncaging as a strategy to prevent brain ischemia," J. Biomed. Opt., Vol. 18, No. 12, 126012-126012, 2013.

    53. Callaway, E. M. and R. Yuste, "Stimulating neurons with light," Current Opinion in Neurobiology, Vol. 12, No. 5, 587-592, Oct. 2002.

    54. Nagel, G., T. Szellas, W. Huhn, S. Kateriya, N. Adeishvili, P. Berthold, D. Ollig, P. Hegemann, and E. Bamberg, "Channelrhodopsin-2, a directly light-gated cation-selective membrane channel," PNAS, Vol. 100, No. 24, 13940-13945, Nov. 2003.

    55. Boyden, E. S., F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, "Millisecond-timescale, genetically targeted optical control of neural activity," Nat. Neurosci., Vol. 8, No. 9, 1263-1268, Sep. 2005.

    56. Nagel, G., M. Brauner, J. F. Liewald, N. Adeishvili, E. Bamberg, and A. Gottschalk, "Light activation of channelrhodopsin-2 in excitable cells of caenorhabditis elegans triggers rapid behavioral responses," Current Biology, Vol. 15, No. 24, 2279-2284, Dec. 2005.

    57. Zhang, Y.-P. and T. G. Oertner, "Optical induction of synaptic plasticity using a light-sensitive channel," Nat. Meth., Vol. 4, No. 2, 139-141, Feb. 2007.

    58. Guo, Z. V., A. C. Hart, and S. Ramanathan, "Optical interrogation of neural circuits in Caenorhabditis elegans," Nat. Meth., Vol. 6, No. 12, 891-896, Dec. 2009.

    59. Rickgauer, J. P., K. Deisseroth, and D. W. Tank, "Simultaneous cellular-resolution optical perturbation and imaging of place cell firing fields," Nat. Neurosci., Vol. 17, No. 12, 1816-1824, Dec. 2014.

    60. Packer, A. M., L. E. Russell, H. W. P. Dalgleish, and M. Häusser, "Simultaneous all-optical manipulation and recording of neural circuit activity with cellular resolution in vivo," Nat. Meth., Vol. 12, No. 2, 140-146, Dec. 2014.

    61. Zhang, F., A. M. Aravanis, A. Adamantidis, L. de Lecea, and K. Deisseroth, "Circuit-breakers: Optical technologies for probing neural signals and systems," Nat. Rev. Neurosci., Vol. 8, No. 8, 577-581, Aug. 2007.

    62. Gradinaru, V., F. Zhang, C. Ramakrishnan, J. Mattis, R. Prakash, I. Diester, I. Goshen, K. R. Thompson, and K. Deisseroth, "Molecular and cellular approaches for diversifying and extending optogenetics," Cell, Vol. 141, No. 1, 154-165, Apr. 2010.

    63. Zhang, F., V. Gradinaru, A. R. Adamantidis, R. Durand, R. D. Airan, L. de Lecea, and K. Deisseroth, "Optogenetic interrogation of neural circuits: Technology for probing mammalian brain structures," Nat. Protocols, Vol. 5, No. 3, 439-456, Mar. 2010.

    64. Zhang, F., L.-P. Wang, M. Brauner, J. F. Liewald, K. Kay, N. Watzke, P. G. Wood, E. Bamberg, G. Nagel, A. Gottschalk, and K. Deisseroth, "Multimodal fast optical interrogation of neural circuitry," Nature, Vol. 446, No. 7136, 633-639, Apr. 2007.

    65. Akerboom, J., N. Carreras Calderón, L. Tian, S. Wabnig, M. Prigge, J. Tolö, A. Gordus, M. B. Orger, K. E. Severi, J. J. Macklin, R. Patel, S. R. Pulver, T. J. Wardill, E. Fischer, C. Schüler, T.-W. Chen, K. S. Sarkisyan, J. S. Marvin, C. I. Bargmann, D. S. Kim, S. Kügler, L. Lagnado, P. Hegemann, A. Gottschalk, E. R. Schreiter, and L. L. Looger, "Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics," Front Mol. Neurosci., Vol. 6, Mar. 2013.

    66. Anikeeva, P., A. S. Andalman, I. Witten, M. Warden, I. Goshen, L. Grosenick, L. A. Gunaydin, L. M. Frank, and K. Deisseroth, "Optetrode: A multichannel readout for optogenetic control in freely moving mice," Nat. Neurosci., Vol. 15, No. 1, 163-170, Jan. 2012.

    67. Peron, S. and K. Svoboda, "From cudgel to scalpel: Toward precise neural control with optogenetics," Nat. Meth., Vol. 8, No. 1, 30-34, Jan. 2011.

    68. Prakash, R., O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, "Two-photon optogenetic toolbox for fast inhibition, excitation and bistable modulation," Nat. Meth., Vol. 9, No. 12, 1171-1179, Dec. 2012.

    69. Yizhar, O., L. E. Fenno, T. J. Davidson, M. Mogri, and K. Deisseroth, "Optogenetics in Neural Systems," Neuron, Vol. 71, No. 1, 9-34, Jul. 2011.

    70. Rhee, A. Y., G. Li, J. Wells, and J. P. Y. Kao, "Photostimulation of sensory neurons of the rat vagus nerve," SPIE BiOS: Biomedical Optics. International Society for Optics and Photonics, Vol. 6854, 68540E-68540E-5, 2008.

    71. Suh, E., A. Izzo Matic, M. Otting, J. Joseph T. Walsh, and C.-P. Richter, "Optical stimulation in mice lacking the TRPV1 channel," SPIE BiOS: Biomedical Optics. International Society for Optics and Photonics, Vol. 7180, 71800S-71800S-5, 2009.

    72. Yao, J., B. Liu, and F. Qin, "Rapid temperature jump by infrared diode laser irradiation for patch-clamp studies," Biophys. J., Vol. 96, No. 9, 3611-3619, May 2009.

    73. Albert, E. S., J. M. Bec, G. Desmadryl, K. Chekroud, C. Travo, S. Gaboyard, F. Bardin, I. Marc, M. Dumas, G. Lenaers, C. Hamel, A. Muller, and C. Chabbert, "TRPV4 channels mediate the infrared laser-evoked response in sensory neurons," J. Neurophysiol., Vol. 107, No. 12, 3227-3234, Jun. 2012.

    74. Richter, C.-P. and X. Tan, "Photons and neurons," Hearing Research, Vol. 311, 72-88, May 2014.

    75. Kamei, Y., M. Suzuki, K. Watanabe, K. Fujimori, T. Kawasaki, T. Deguchi, Y. Yoneda, T. Todo, S. Takagi, T. Funatsu, and S. Yuba, "Infrared laser-mediated gene induction in targeted single cells in vivo," Nat. Meth., Vol. 6, No. 1, 79-81, Jan. 2009.

    76. Young, S. R., M. Dyson, and P. Bolton, "Effect of light on calcium uptake by macrophages," Laser Therapy, Vol. 2, No. 2, 53-57, 1990.

    77. Lubart, H. F. R., "Effect of light on calcium transport in bull sperm cells," Journal of Photochemistry and Photobiology. B, Biology, Vol. 15, No. 4, 337-41, 1992.

    78. Breitbart, H., T. Levinshal, N. Cohen, H. Friedmann, and R. Lubart, "Changes in calcium transport in mammalian sperm mitochondria and plasma membrane irradiated at 633 nm (HeNe laser)," Journal of Photochemistry and Photobiology B: Biology, Vol. 34, No. 2-3, 117-121, Jul. 1996.

    79. Rachel Lubart, H. F., "Changes in calcium transport in mammalian sperm mitochondria and plasma membranes caused by 780 nm irradiation," Lasers in Surgery and Medicine, Vol. 21, No. 5, 493-9, 1997.

    80. Karu, T., "Derepression of the Genome after irradiation of human lymphocytes with He-Ne laser," Laser Therapy, Vol. 4, No. 1, 5-24, 1992.

    81. Schwartz, F., M. Adamek, C. Brodie, and A. Shainberg, "Effect of low-energy laser irradiation on cytokine secretion from skeletal muscle cells: Involvement of calcium in the process," BiOS Europe'97. International Society for Optics and Photonics, Vol. 3198, 48-54, 1997.

    82. Schwartz, F., C. Brodie, E. Appel, G. Kazimirsky, and A. Shainberg, "Effect of helium/neon laser irradiation on nerve growth factor synthesis and secretion in skeletal muscle cultures," Journal of Photochemistry and Photobiology B: Biology, Vol. 66, No. 3, 195-200, Apr. 2002.

    83. Alexandratou, E., D. Yova, P. Handris, D. Kletsas, and S. Loukas, "Human fibroblast alterations induced by low power laser irradiation at the single cell level using confocal microscopy," Photochemical & Photobiological Sciences, Vol. 1, No. 8, 547-552, Jul. 2002.

    84. Yang, W.-Z., J.-Y. Chen, J.-T. Yu, and L.-W. Zhou, "Effects of low power laser irradiation on intracellular calcium and histamine release in RBL-2H3 mast cells," Photochemistry and Photobiology, Vol. 83, No. 4, 979-984, Jul. 2007.

    85. Lubart, R., R. Lavi, H. Friedmann, and S. Rochkind, "Photochemistry and photobiology of light absorption by living cells," Photomedicine and Laser Surgery, Vol. 24, No. 2, 179-185, Apr. 2006.

    86. Cohen, N., R. Lubart, S. Rubinstein, and H. Breitbart, "Light irradiation of mouse spermatozoa: Stimulation of in vitro fertilization and calcium signals," Photochemistry and Photobiology, Vol. 68, No. 3, 407-413, Sep. 1998.

    87. Lavi, R., A. Shainberg, H. Friedmann, V. Shneyvays, O. Rickover, M. Eichler, D. Kaplan, and R. Lubart, "Low energy visible light induces reactive oxygen species generation and stimulates an increase of intracellular calcium concentration in cardiac cells," J. Biol. Chem., Vol. 278, No. 42, 40917-40922, Oct. 2003.

    88. Dittami, G. M., S. M. Rajguru, R. A. Lasher, R. W. Hitchcock, and R. D. Rabbitt, "Intracellular calcium transients evoked by pulsed infrared radiation in neonatal cardiomyocytes," J. Neurophysiol., Vol. 589, No. 6, 1295-1306, Mar. 2011.

    89. Lumbreras, V., E. Bas, C. Gupta, and S. M. Rajguru, "Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling," J. Neurophysiol., Vol. 112, No. 6, 1246-1255, Sep. 2014.

    90. Iwanaga, S., N. Smith, K. Fujita, S. Kawata, and O. Nakamura, "Single-pulse cell stimulation with a near-infrared picosecond laser," Applied Physics Letters, Vol. 87, 243901, Dec. 2005.

    91. Iwanaga, S., T. Kaneko, K. Fujita, N. Smith, O. Nakamura, T. Takamatsu, and S. Kawata, "Location-dependent photogeneration of calcium waves in HeLa cells," Cell Biochem Biophys, Vol. 45, No. 2, 167-176, Jun. 2006.

    92. Baumgart, J., W. Bintig, A. Ngezahayo, H. Lubatschowski, and A. Heisterkamp, "Fs-laser-induced Ca2+ concentration change during membrane perforation for cell transfection," Optics Express, Vol. 18, No. 3, 2219, Feb. 2010.

    93. Iwanaga, S., N. I. Smith, K. Fujita, and S. Kawata, "Slow Ca2+ wave stimulation using low repetition rate femtosecond pulsed irradiation," Optics Express, Vol. 14, No. 2, 717, 2006.

    94. Zhou, M., E. L. Zhao, H. F. Yang, A. H. Gong, J. K. Di, and Z. J. Zhang, "Generation of calcium waves in living cells induced by 1 kHz femtosecond laser protuberance microsurgery," Laser Phys., Vol. 19, No. 7, 1470-1474, Jul. 2009.

    95. Vogel, A., "Nonlinear absorption: intraocular microsurgery and laser lithotripsy," Phys. Med. Biol., Vol. 42, No. 5, 895, 1997.

    96. Vogel, A., J. Noack, K. Nahen, D. Theisen, S. Busch, U. Parlitz, D. X. Hammer, G. D. Noojin, B. A. Rockwell, and R. Birngruber, "Energy balance of optical breakdown in water at nanosecond to femtosecond time scales," Applied Physics B: Lasers and Optics, Vol. 68, No. 2, 271-280, 1999.

    97. Iwanaga, S., N. I. Smith, K. Fujita, T. Kaneko, M. Oyamada, T. Takamatsu, S. Kawata, and O. Nakamura, "Stimulation of living cells by femtosecond near-infrared laser pulses," High-Power Lasers and Applications, 122-128, 2003.

    98. Zhao, Y., Y. Zhang, X. Liu, X. Lv, W. Zhou, Q. Luo, and S. Zeng, "Photostimulation of astrocytes with femtosecond laser pulses," Optics Express, Vol. 17, No. 3, 1291, Feb. 2009.

    99. Rizzuto, R. and T. Pozzan, "Microdomains of intracellular Ca2+: Molecular determinants and functional consequences," Physiological Reviews, Vol. 86, No. 1, 369-408, Jan. 2006.

    100. He, H., S. Li, S. Wang, M. Hu, Y. Cao, and C. Wang, "Manipulation of cellular light from green fluorescent protein by a femtosecond laser," Nat. Photon., Vol. 6, No. 10, 651-656, Oct. 2012.

    101. He, H., S. K. Kong, and K. T. Chan, "Identification of source of calcium in HeLa cells by femtosecond laser excitation," J. Biomed. Opt., Vol. 15, No. 5, 057010-057010-5, 2010.

    102. He, H., K. T. Chan, and S. K. Kong, "Role of nuclear tubule on the apoptosis of HeLa cells induced by femtosecond laser," Applied Physics Letters, Vol. 96, No. 22, 223701, May 2010.

    103. Watanabe, W., N. Arakawa, S. Matsunaga, T. Higashi, K. Fukui, K. Isobe, and K. Itoh, "Femtosecond laser disruption of subcellular organelles in a living cell," Optics Express, Vol. 12, No. 18, 4203, 2004.

    104. He, H., K. T. Chan, S. K. Kong, and R. K. Y. Lee, "Mechanism of oxidative stress generation in cells by localized near-infrared femtosecond laser excitation," Applied Physics Letters, Vol. 95, No. 23, 233702, Dec. 2009.

    105. He, H., S. Wang, X. Li, S. Li, M. Hu, Y. Cao, and C.-Y. Wang, "Ca2+ waves across gaps in non-excitable cells induced by femtosecond laser exposure," Applied Physics Letters, Vol. 100, No. 17, 173704, Apr. 2012.

    106. He, H., K. Nakagawa, Y. Wang, Y. Hosokawa, and K. Goda, "Mechanism for microtsunami-induced intercellular mechanosignalling," Nat. Photon., Vol. 9, No. 10, 623-623, Oct. 2015.

    107. Zhao, Y., Y. Zhang, W. Zhou, X. Liu, S. Zeng, and Q. Luo, "Characteristics of calcium signaling in astrocytes induced by photostimulation with femtosecond laser," J. Biomed. Opt., Vol. 15, No. 3, 035001-035001-5, 2010.

    108. Compton, J. L., J. C. Luo, H. Ma, E. Botvinick, and V. Venugopalan, "High-throughput optical screening of cellular mechanotransduction," Nat. Photon., Vol. 8, No. 9, 710-715, Sep. 2014.

    109. Bianchi, K., A. Rimessi, A. Prandini, G. Szabadkai, and R. Rizzuto, "Calcium and mitochondria: mechanisms and functions of a troubled relationship," Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1742, No. 1-3, 119-131, Dec. 2004.

    110. Tirlapur, U. K., K. König, C. Peuckert, R. Krieg, and K.-J. Halbhuber, "Femtosecond near-infrared laser pulses elicit generation of reactive oxygen species in mammalian cells leading to apoptosis-like death," Experimental Cell Research, Vol. 263, No. 1, 88-97, Feb. 2001.

    111. Yan, W., H. He, Y. Wang, Y. Wang, M. Hu, and C. Wang, "Controllable generation of reactive oxygen species by femtosecond-laser irradiation," Applied Physics Letters, Vol. 104, No. 8, 083703, Feb. 2014.

    112. Yoon, J., S. Ryu, S. Lee, and C. Choi, "Cytosolic irradiation of femtosecond laser induces mitochondria-dependent apoptosis-like cell death via intrinsic reactive oxygen cascades," Scientific Reports, Vol. 5, 8231, Feb. 2015.

    113. Ando, J., N. I. Smith, K. Fujita, and S. Kawata, "Photogeneration of membrane potential hyperpolarization and depolarization in non-excitable cells," Eur. Biophys. J., Vol. 38, No. 2, 255-262, Jan. 2009.

    114. Wang, Y., H. He, S. Li, D. Liu, B. Lan, M. Hu, Y. Cao, and C. Wang, "All-optical regulation of gene expression in targeted cells," Sci. Rep., Vol. 4, Jun. 2014.

    115. Smith, N. I., Y. Kumamoto, S. Iwanaga, J. Ando, K. Fujita, and S. Kawata, "A femtosecond laser pacemaker for heart muscle cells," Optics Express, Vol. 16, No. 12, 8604, Jun. 2008.

    116. Hirase, H., V. Nikolenko, J. H. Goldberg, and R. Yuste, "Multiphoton stimulation of neurons," J. Neurophysiol., Vol. 51, No. 3, 237-247, Jun. 2002.

    117. Smith, N. I., S. Iwanaga, T. Beppu, K. Fujita, O. Nakamura, and S. Kawata, "Femtosecond laser-induced calcium release in neural-type cells," Biomedical Optics 2005. International Society for Optics and Photonics, Vol. 5705, 1-6, 2005.

    118. Day, D., C. G. Cranfield, and M. Gu, "High-speed fluorescence imaging and intensity profiling of femtosecond-induced calcium transients," International Journal of Biomedical Imaging, Vol. 2006, e93438, Mar. 2006.

    119. Smith, N. I., S. Iwanaga, T. Beppu, K. Fujita, O. Nakamura, and S. Kawata, "Photostimulation of two types of Ca2+ waves in rat pheochromocytoma PC12 cells by ultrashort pulsed near-infrared laser irradiation," Laser Phys. Lett., Vol. 3, No. 3, 154, Mar. 2006.

    120. Zhou, W., X. Liu, X. L¨u, J. Li, Q. Luo, and S. Zeng, "Monitor and control of neuronal activities with femtosecond pulse laser," Chin. Sci. Bull., Vol. 53, No. 5, 687-694, Mar. 2008.

    121. Liu, X., X. Lv, S. Zeng, W. Zhou, and Q. Luo, "Noncontact and nondestructive identification of neural circuits with a femtosecond laser," Applied Physics Letters, Vol. 94, No. 6, 061113, Feb. 2009.

    122. Parys, B., A. Côté V. Gallo, P. De Koninck, and A. Sík, "Intercellular calcium signaling between astrocytes and oligodendrocytes via gap junctions in culture," Neuroscience, Vol. 167, No. 4, 1032-1043, Jun. 2010.

    123. Zhao, Y., X. Liu, Y. Zhang, W. Zhou, and S. Zeng, "Modulation of synchronous calcium oscillations in hippocampal neurons by photostimulation of astrocytes with femtosecond laser," Chin. Sci. Bull., Vol. 55, No. 30, 3436-3440, Nov. 2010.