title: Evoked centripetal Ca(2+) mobilization in cardiac Purkinje cells: insight from a model of three Ca(2+) release regions.
abstract: Despite strong suspicion that abnormal Ca(2+) handling in Purkinje cells (P-cells) is implicated in life-threatening forms of ventricular tachycardias, the mechanism underlying the Ca(2+) cycling of these cells under normal conditions is still unclear. There is mounting evidence that P-cells have a unique Ca(2+) handling system. Notably complex spontaneous Ca(2+) activity was previously recorded in canine P-cells and was explained by a mechanistic hypothesis involving a triple layered system of Ca(2+) release channels. Here we examined the validity of this hypothesis for the electrically evoked Ca(2+) transient which was shown, in the dog and rabbit, to occur progressively from the periphery to the interior of the cell. To do so, the hypothesis was incorporated in a model of intracellular Ca(2+) dynamics which was then used to reproduce numerically the Ca(2+) activity of P-cells under stimulated conditions. The modelling was thus performed through a 2D computational array that encompassed three distinct Ca(2+) release nodes arranged, respectively, into three consecutive adjacent regions. A system of partial differential equations (PDEs) expressed numerically the principal cellular functions that modulate the local cytosolic Ca(2+) concentration (Cai). The apparent node-to-node progression of elevated Cai was obtained by combining Ca(2+) diffusion and 'Ca(2+)-induced Ca(2+) release'. To provide the modelling with a reliable experimental reference, we first re-examined the Ca(2+) mobilization in swine stimulated P-cells by 2D confocal microscopy. As reported earlier for the dog and rabbit, a centripetal Ca(2+) transient was readily visible in 22 stimulated P-cells from six adult Yucatan swine hearts (pacing rate: 0.1 Hz; pulse duration: 25 ms, pulse amplitude: 10% above threshold; 1 mm Ca(2+); 35°C; pH 7.3). An accurate replication of the observed centripetal Ca(2+) propagation was generated by the model for four representative cell examples and confirmed by statistical comparisons of simulations against cell data. Selective inactivation of Ca(2+) release regions of the computational array showed that an intermediate layer of Ca(2+) release nodes with an ~30-40% lower Ca(2+) activation threshold was required to reproduce the phenomenon. Our computational analysis was therefore fully consistent with the activation of a triple layered system of Ca(2+) release channels as a mechanism of centripetal Ca(2+) signalling in P-cells. Moreover, the model clearly indicated that the intermediate Ca(2+) release layer with increased sensitivity for Ca(2+) plays an important role in the specific intracellular Ca(2+) mobilization of Purkinje fibres and could therefore be a relevant determinant of cardiac conduction.
authors.affiliation: B. D. Stuyvers: Memorial University, Faculty of Medicine, Division of BioMedical Sciences, 300 Prince Phillip Bd, St John's, NL, A1B 3V6, Canada. stuyvers@mun.ca.
authors.forename: Kazi T
authors.initials: KT
authors.lastname: Haq
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Daniels
authors.forename: Lawson S
authors.initials: LS
authors.lastname: Miller
authors.forename: Masahito
authors.initials: M
authors.lastname: Miura
authors.forename: Henk E D J
authors.initials: HE
authors.lastname: ter Keurs
authors.forename: Sharene D
authors.initials: SD
authors.lastname: Bungay
authors.forename: Bruno D
authors.initials: BD
authors.lastname: Stuyvers
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D003593:Cytoplasm / Q000378:metabolism; D004058:Diffusion; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008955:Models, Cardiovascular; D011690:Purkinje Fibers / Q000378:metabolism*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D015220:Calcium Channels
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