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1. Calcium and IP3 dynamics in cardiac myocytes: Experimental and computational perspectives and approaches

Author

Felix eHohendanner, Andrew D McCulloch, Lothar A Blatter, and Anushka P Michailova

Subjects
cardiomyocyte, Ca2+, excitation-contraction coupling, IP3, excitation-transcription coupling, Therapeutics. Pharmacology, RM1-950
Abstract

Calcium plays a crucial role in excitation-contraction coupling (ECC), but it is also a pivotal second messenger activating Ca2+-dependent transcription factors in a process termed excitation-transcription coupling (ETC). Evidence accumulated over the past decade indicates a pivotal role of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release in the regulation of cytosolic and nuclear Ca2+ signals. IP3 is generated by stimulation of plasma membrane receptors that couple to phospholipase C (PLC), liberating IP3 from phosphatidylinositol 4,5-bisphosphate (PIP2). An intriguing aspect of IP3 signaling is the presence of the entire PIP2-PLC-IP3 signaling cascade as well as the presence of IP3Rs at the inner and outer membranes of the nuclear envelope (NE) which functions as a Ca2+ store. The observation that the nucleus is surrounded by its own putative Ca2+ store raises the possibility that nuclear IP3-dependent Ca2+ release plays a critical role in ETC. This provides a potential mechanism of regulation that acts locally and autonomously from the global cytosolic Ca2+ signal underlying ECC. Moreover, there is evidence that: (i) the sarcoplasmic reticulum (SR) and NE are a single contiguous Ca2+ store; (ii) the nuclear pore complex is the major gateway for Ca2+ and macromolecules to pass between the cytosol and the nucleoplasm; (iii) the inner membrane of the NE hosts key Ca2+ handling proteins including the Na+/Ca2+ exchanger (NCX)/GM1 complex, ryanodine receptors (RyRs), nicotinic acid adenine dinucleotide phosphate receptors (NAADPRs), Na+/K+ ATPase and Na+/H+ exchanger. Thus, it appears that the nucleus represents a Ca2+ signaling domain equipped with its own ion channels and transporters that allow for complex local Ca2+ signals. Many experimental and modeling approaches have been used for the study of intracellular Ca2+ signaling but the key to understanding of the dual role of Ca2+ mediating ECC and ECT lays in quantitative differences of local [Ca2+

Published
2014
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2. Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum.

Author

Yuhui Cheng, Zeyun Yu, Masahiko Hoshijima, Michael J Holst, Andrew D McCulloch, J Andrew McCammon, and Anushka P Michailova

Subjects
Biology (General), QH301-705.5
Abstract

The t-tubules of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca(2+)). To investigate how the t-tubule microanatomy and the distribution of membrane Ca(2+) flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca(2+) signaling, buffering and diffusion in rat ventricular myocytes. The transverse-axial t-tubule geometry was derived from light microscopy structural data. To solve the nonlinear reaction-diffusion system we extended SMOL software tool (http://mccammon.ucsd.edu/smol/). The analysis suggests that the quantitative understanding of the Ca(2+) signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca(2+) flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca(2+) buffers, including the Ca(2+) indicator dye. In agreement with experiment, in the presence of fluorescence dye and inhibited sarcoplasmic reticulum, the lack of detectible differences in the depolarization-evoked Ca(2+) transients was found when the Ca(2+) flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca(2+) signals are predicted. Even at modest elevation of Ca(2+), reached during Ca(2+) influx, large and steep Ca(2+) gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca(2+) flux density along the cell membrane support initiation and propagation of Ca(2+) waves in rat myocytes.

Published
2010
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3. Contributors

Author

Philip Aagaard, Dominic James Abrams, Hugues Abriel, Wayne O. Adkisson, Esperanza Agullo-Pascual, Francisco J. Alvarado, Ahmad S. Amin, Charles Antzelevitch, Justus M.B. Anumonwo, Luciana Armaganijan, Arash Arya, Samuel Asirvatham, Felipe Atienza, Peter H. Backx, Lisa M. Ballou, Elise Balse, Sujata Balulad, Andrea Barbuti, Gust H. Bardy, Guillaume Bassil, David G. Benditt, Omer Berenfeld, Donald M. Bers, Ofer Binah, Frank Bogun, Rossana Bongianino, Noel G. Boyle, Patrick M. Boyle, Günter Breithardt, Marisa Brini, Peter R. Brink, Pedro Brugada, Eric Buch, Feliksas F. Bukauskas, Hugh Calkins, David J. Callans, Sean M. Caples, Ernesto Carafoli, William A. Catterall, Marina Cerrone, Arnaud Chaumeil, Caressa Chen, Lan S. Chen, Peng-Sheng Chen, Jianding Cheng, Nipavan Chiamvimonvat, David J. Christini, Aman Chugh, Andreu M. Climent, Ira S. Cohen, Stuart J. Connolly, Lebron Cooper, Eric M. Crespo, Lia Crotti, Thomas A. Csepe, Frank Cuoco, Anne B. Curtis, Ralph J. Damiano, Dawood Darbar, Mithilesh K. Das, Andre d’Avila, Mario Delmar, Eva Delpón, Marco Denegri, Arnaud Denis, Nicolas Derval, Isabelle Deschênes, Abhishek Deshmukh, Luigi Di Biase, Timm M. Dickfeld, Hans Dierckx, Borislav Dinov, Sanjay Dixit, Dobromir Dobrev, Remi Dubois, Lars Eckardt, Andrew G. Edwards, Kenneth A. Ellenbogen, Patrick T. Ellinor, N.A. Mark Estes, Larissa Fabritz, Vadim V. Fedorov, Antonio B. Fernandez, Elvis Teijeira Fernández, David Filgueiras-Rama, Michael C. Fishbein, Glenn I. Fishman, David S. Frankel, Paul Friedman, Antonio Frontera, Apoor S. Gami, Paul Garabelli, Alfred L. George, Edward P. Gerstenfeld, Sigfus Gizurarson, Michael R. Gold, Jeffrey J. Goldberger, Andrew Grace, Guido Grassi, Ruth Ann Greenfield, Wendy L. Gross, Blair P. Grubb, María S. Guillem, Sándor Györke, Michel Haïssaguerre, Johan Hake, Henry R. Halperin, Brian J. Hansen, Stéphane Hatem, David L. Hayes, Jordi Heijman, Todd J. Herron, Gerhard Hindricks, Mélèze Hocini, Stefan H. Hohnloser, David R. Holmes, Masahiko Hoshijima, Thomas J. Hund, Mathew D. Hutchinson, Leonard Ilkhanoff, Jodie Ingles, James E. Ip, Warren M. Jackman, Nicholas Jackson, Pierre Jaïs, José Jalife, Bong Sook Jhun, Roy M. John, Monique Jongbloed, Luc Jordaens, Jonathan M. Kalman, Timothy J. Kamp, Mohamed H. Kanj, Suraj Kapa, Beverly Karabin, Ioannis Karakikes, Demosthenes G. Katritsis, Kuljeet Kaur, Paulus Kirchhof, André G. Kléber, George J. Klein, Peter Kohl, Jayanthi N. Koneru, Jacob S. Koruth, Andrew D. Krahn, Trine Krogh-Madsen, Karl Heinz Kuck, Saurabh Kumar, Alexander Kushnir, Neal K. Lakdawala, Zachary W.M. Laksman, Rakesh Latchamsetty, Dennis H. Lau, Bruce B. Lerman, Richard Z. Lin, Shien-Fong Lin, Mark S. Link, Bin Liu, Christopher F. Liu, Deborah J. Lockwood, Anatoli N. Lopatin, Steven A. Lubitz, Rajiv Mahajan, Jonathan C. Makielski, Marek Malik, Francis E. Marchlinski, Steven M. Markowitz, Barry J. Maron, Martin S. Maron, Steven O. Marx, Stéphane Massé, Andrew D. McCulloch, Pippa McKelvie-Sebileau, Spencer J. Melby, Andreas Metzner, Anushka P. Michailova, Gregory F. Michaud, John M. Miller, Jyotsna Mishra, Raul D. Mitrani, Peter J. Mohler, Fred Morady, Robert J. Myerburg, Hiroshi Nakagawa, Chrishan Joseph Nalliah, Kumaraswamy Nanthakumar, Carlo Napolitano, Sanjiv M. Narayan, Andrea Natale, Stanley Nattel, Saman Nazarian, Thao P. Nguyen, Akihiko Nogami, Sami F. Noujaim, Karine Nubret Le Coniat, Brian Olshansky, Jin O-Uchi, Gavin Y. Oudit, Feifan Ouyang, Cevher Ozcan, Douglas L. Packer, Sandeep V. Pandit, Alexander V. Panfilov, David S. Park, Bence Patocskai, Dainius H. Pauza, Neringa Pauziene, Jonathan P. Piccini, Geoffrey S. Pitt, Sunny S. Po, Abhiram Prasad, Silvia G. Priori, Przemysław B. Radwański, Wouter-Jan Rappel, Michelle Reiser, Alejandro Jimenez Restrepo, Richard B. Robinson, Dan M. Roden, Michael R. Rosen, Raphael Rosso, Yoram Rudy, Kristina Rysevaite-Kyguoliene, Hani N. Sabbah, Frederic Sacher, Frank B. Sachse, Ardan M. Saguner, Prashanthan Sanders, Michael C. Sanguinetti, Pasquale Santangeli, Mohammad Sarraf, Jonathan Satin, Martin Jan Schalij, Benjamin J. Scherlag, Matthew R. Schill, J. William Schleifer, Richard B. Schuessler, Peter J. Schwartz, Timon Seeger, Christopher Semsarian, Gino Seravalle, Ashok J. Shah, Robin M. Shaw, Mark J. Shen, Win–Kuang Shen, Shey-Shing Sheu, Kalyanam Shivkumar, Jennifer N.A. Silva, Allan C. Skanes, Kyoko Soejima, Virend K. Somers, Dan Sorajja, Stavros Stavrakis, Christian Steinberg, Lynne Warner Stevenson, William G. Stevenson, Michael O. Sweeney, Charles Swerdlow, Masateru Takigawa, Juan Tamargo, Harikrishna Tandri, Usha B. Tedrow, Nathaniel Thompson, Paul D. Thompson, Gordon F. Tomaselli, Jeffrey A. Towbin, Natalia A. Trayanova, Martin Tristani-Firouzi, Zian H. Tseng, Akiko Ueda, Héctor H. Valdivia, Virginijus Valiunas, Christian van der Werf, George F. Van Hare, David Vidmar, Sami Viskin, Niels Voigt, Edward P. Walsh, Paul J. Wang, Xander H.T. Wehrens, Mark S. Weiss, Arthur A.M. Wilde, Bruce L. Wilkoff, Y. Joseph Woo, Joseph C. Wu, Raymond Yee, Junaid A.B. Zaman, Manuel Zarzoso, Emily P. Zeitler, Katja Zeppenfeld, Tarek Zghaib, Xiao-Dong Zhang, and Douglas P. Zipes

Published
2018
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