Evoked centripetal Ca²⁺ mobilization in cardiac Purkinje cells: insight from a model of three Ca²⁺ release regions

Abstract

Key points• Abnormal oscillations of calcium (Ca 2+ ) concentration in cardiac Purkinje cells (P-cells) have been associated with life-threatening arrhythmias, but the mechanism by which these cells control their Ca 2+ level in normal conditions remains unknown.• We modelled our previous hypothesis that the principal intracellular Ca 2+ compartment (endoplasmic reticulum; ER) which governs intracellular Ca 2+ concentration, formed, in P-cells, three concentric and adjacent layers, each including a distinct Ca 2+ release channel. We then tested the model against typical Ca 2+ variations observed in stimulated P-cells.• We found in swine P-cells, as in the rabbit and dog, that stimulation evokes an elevation of Ca 2+ concentration first under the membrane , which then propagates to the interior of the cell.• Our mathematical model could reproduce accurately this typical 'centripetal' Ca 2+ spread, hence supporting (1) the existence of the '3 layered' Ca 2+ compartment, and (2) its central role in the regulation of Ca 2+ concentration in P-cells.• To model the 'centripetal' Ca 2+ spread, local variations of Ca 2+ concentration were calculated for a virtual cell environment encompassing three different regions that mimicked the three layers of ER in P-cells. Various tests of the model revealed that the second intermediate layer was essential for 'forwarding' the Ca 2+ elevation from the periphery to the cell centre.• This novel finding suggests that a thin intermediate layer of specific ER Ca 2+ channels controls the entire Ca 2+ signalling of P-cells. Because Ca 2+ plays a role in the electric properties of P-cells, any abnormality affecting this intermediate region is likely to be pro-arrhythmic and could explain the origin of serious cardiac arrhythmias known to start in the Purkinje fibres.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,

Cardiac Purkinje fibers and arrhythmias; The GK Moe Award Lecture 2015

“…EC coupling proteins 10 ). In fact, using differential transcriptional profiling techniques, Atkinson et al 11 report significant differences in mRNA abundance in rabbit Purkinje versus Ventricular myocardium.…”

Small caliber arterial endothelial cells calcium signals elicited by PAR2 are preserved from endothelial dysfunction

“…We report kinetic properties for peripheral and central events that infer Ca 2+ -release (t rise ) and Ca 2+ -uptake (t 1/2 ) functions are different for each event type. IP 3 -and Ca 2+sensitivities differ between the three types of IP 3 R (Taylor et al 2014) and a triple layer system of IP 3 R and ryanodine receptors models Ca 2+ -signaling in cardiac purkinje fibers (Haq et al 2013). In small caliber arteries, IP 3 R distributed near their Ca 2+ -signals downstream target, that is, K Ca 2.3 was widespread on the cell surface whereas Figure 2.…”

“…) and a triple layer system of IP 3 R and ryanodine receptors models Ca 2+ ‐signaling in cardiac purkinje fibers (Haq et al. ). In small caliber arteries, IP 3 R distributed near their Ca 2+ ‐signals downstream target, that is, K Ca 2.3 was widespread on the cell surface whereas K Ca 3.1 localized to myoendothelial projections (Dora et al.…”

“…Intracellular Ca 2+ dynamics were recorded by 2‐dimension (2D) CM (Haq et al. ). Briefly, Ca 2+ events were measured as elevations of Ca 2+ ‐Fluo4 fluorescence along the mid planar region of EC.…”

Arrhythmia: 100 years on from George Ralph Mines

“…Although abnormal oscillations of calcium in Purkinje cells are thought to be life threatening, the mechanism by which these cells control intracellular calcium is still poorly understood. Using a combination of mathematical modelling and experimental techniques, Haq et al (2013) were able to support the hypothesis that a thin intermediate layer of specific ER‐Ca 2+ channels controls the entire intracellular Ca 2+ concentration in the Purkinje cell network. The implication being that an abnormality in this region (e.g.…”