title: A modified local control model for Ca2+ transients in cardiomyocytes: junctional flux is accompanied by release from adjacent non-junctional RyRs.
abstract: Excitation-contraction coupling in cardiomyocytes requires Ca(2+) influx through dihydropyridine receptors in the sarcolemma, which gates Ca(2+) release through sarcoplasmic ryanodine receptors (RyRs). Ca(2+) influx, release and diffusion produce a cytosolic Ca(2+) transient. Here, we investigated the relationship between Ca(2+) transients and the spatial arrangement of the sarcolemma including the transverse tubular system (t-system). To accomplish this, we studied isolated ventricular myocytes of rabbit, which exhibit a heterogeneously distributed t-system. We developed protocols for fluorescent labeling and triggered two-dimensional confocal microscopic imaging with high spatiotemporal resolution. From sequences of microscopic images, we measured maximal upstroke velocities and onset times of local Ca(2+) transients together with their distance from the sarcolemma. Analyses indicate that not only sarcolemmal release sites, but also those that are within 1 μm of the sarcolemma actively release Ca(2+). Our data also suggest that release does not occur at sites further than 2.5 μm from the sarcolemma. The experimental data are in agreement with results from a mathematical model of Ca(2+) release and diffusion. Our findings can be explained by a modified local control model, which constrains the region of regenerative activation of non-junctional RyR clusters. We believe that this model will be useful for describing excitation-contraction coupling in cardiac myocytes with a sparse t-system, which includes those from diseased heart tissue as well as atrial myocytes of some species.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95S 2000E, Salt Lake City, UT 84112, USA.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Torres
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95S 2000E, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, 20S 2030E, Salt Lake City, UT 84112, USA. Electronic address: frank.sachse@utah.edu.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Sachse
authors.affiliation: Department of Pharmacology, UC Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Leighton T
authors.initials: LT
authors.lastname: Izu
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95S 2000E, Salt Lake City, UT 84112, USA; Department of Physiology, University of Utah, 420 Chipeta Way, Salt Lake City, UT 84108, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Spitzer
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95S 2000E, Salt Lake City, UT 84112, USA; Division of Cardiology, University of Utah, 30N 1900E, Salt Lake City, UT 84132, USA. Electronic address: bridge@cvrti.utah.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Bridge
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D056966:Excitation Contraction Coupling; D006352:Heart Ventricles / Q000166:cytology; D008954:Models, Biological; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Calcium release; Cardiac myocyte; Excitation–contraction coupling; Sarcolemma; Transverse tubular system