Diastolic calcium release controls the beating rate of rabbit sinoatrial node cells: numerical modeling of the coupling process - PubMed (original) (raw)

Diastolic calcium release controls the beating rate of rabbit sinoatrial node cells: numerical modeling of the coupling process

Victor A Maltsev et al. Biophys J. 2004 Apr.

Abstract

Recent studies employing Ca2+ indicators and confocal microscopy demonstrate substantial local Ca2+ release beneath the cell plasma membrane (subspace) of sinoatrial node cells (SANCs) occurring during diastolic depolarization. Pharmacological and biophysical experiments have suggested that the released Ca2+ interacts with the plasma membrane via the ion current (INaCa) produced by the Na+/Ca2+ exchanger and constitutes an important determinant of the pacemaker rate. This study provides a numerical validation of the functional importance of diastolic Ca2+ release for rate control. The subspace Ca2+ signals in rabbit SANCs were measured by laser confocal microscopy, averaged, and calibrated. The time course of the subspace [Ca2+] displayed both diastolic and systolic components. The diastolic component was mainly due to the local Ca2+ releases; it was numerically approximated and incorporated into a SANC cellular electrophysiology model. The model predicts that the diastolic Ca2+ release strongly interacts with plasma membrane via INaCa and thus controls the phase of the action potential upstroke and ultimately the final action potential rate.

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Figures

FIGURE 1

FIGURE 1

Ca2+ signals across the cells as identified by line-scanning confocal microscopy. The scan line was oriented across the cell so that it crossed the longitudinal axis of the cell at approximately one-half of the cell depth (inset). Arrows on the confocal image show local Ca2+ releases in the submembrane space during diastolic depolarization. The blue line shows simultaneous recording of the membrane potential measured by the perforated patch-clamp technique.

FIGURE 2

FIGURE 2

Ca2+ signaling identified by confocal line-scan imaging of SANCs in a subsarcolemmal space. The scanned line was oriented along to the longitudinal axis of the cell close to the plasma membrane (inset). The diastolic Ca2+ releases are indicated by arrows on the image. The respective trace of the average Ca2+ signal (in F/_F_0 scale) processed from the whole image width is shown on the bottom panel.

FIGURE 3

FIGURE 3

The two distinct components of Ca2+ signaling in submembrane space: D, the diastolic Ca2+ release and S, the systolic Ca2+ release (right panels), as identified by averaging the raw F/_F_0 traces (superimposed, left panels) recorded by line-scanning confocal microscopy in four cells. The traces were split into two-cycle fragments by custom-made software and centered, assigning time = 0 for the peak in the middle (see dashed line marked as t = 0). Numbers of superimposed traces are 15, 9, 8, and 14 (left panels, from top to bottom).

FIGURE 4

FIGURE 4

Increase in SANC beating rate on introduction of the spontaneous Ca2+ release component, _j_spont, described by Eq. 2 (see text), into the model. (A) Subspace [Ca2+], _Ca_sub, and membrane potential, _V_m, generated by the original model of Kurata et al. (2002) from Eq. 1. (B) _Ca_sub and _V_m simulations of the same model but with introduced spontaneous Ca2+ release. The time course for _P_phase(t), described by Eq. 3, is also shown (blue line). The beating rate increased from 195.4 bpm to 246.7 bpm with the introduction of _j_spont with the following parameters: _P_rel,spont = 5 ms−1, _t_width = 150 ms, and _t_phase = 150 ms.

FIGURE 5

FIGURE 5

Our variant of SANC model with the diastolic Ca2+ release and adjusted membrane conductance and Ca2+ handling parameters to be in line with experimental data (left side marked as _+ Spontaneous Ca_2+ Release) and its negative chronotropic response on the complete blockade of the spontaneous release (_j_spont = 0) simulating ryanodine effect. Shown are simulated traces for subspace [Ca2+], _Ca_sub, and membrane potential, _V_m, changes. For model parameters see text. T is the action potential period; bpm is beats per min.

FIGURE 6

FIGURE 6

The AP upstroke phase follows the phase of spontaneous Ca2+ release (_t_phase) upon introduction of spontaneous Ca2+ release into the model. Shown are superimposed simulated traces of [Ca2+] changes in subspace (_Ca_sub) along with respective APs generated with varying phase of the diastolic release (_t_phase, shown at peaks of _Ca_sub traces). (Inset) Plot of the first AP period (T) as a function, _t_phase.

FIGURE 7

FIGURE 7

The phase and the amplitude of the diastolic Ca2+ release control the steady-state rate of AP firing. The family of plots shows relationships of cycle period (or respective SANC rate, right scale) versus the phase of the diastolic release (_t_phase in Eq. 3) for various Ca2+ release amplitude determined by _P_rel,spont (in ms−1) in Eq. 2.

FIGURE 8

FIGURE 8

NCX transmits Ca2+ signals to the plasma membrane. (A) Complete AP cycle (_V_m) along with simulated ion currents that have inward direction during diastolic depolarization (DD), namely, current produced by the Na+/Ca2+ exchanger, _I_NaCa; L-type Ca2+ current, _I_CaL; T-type Ca2+ current, _I_CaT; background Na+ and Ca2+ currents _I_bNa and _I_bCa; hyperpolarization-activated _I_f current; and sustained inward current, _I_st. _I_NaCa remains the largest inward current during DD until the membrane potential reaches −32.8 mV (i.e., _I_CaL activation threshold). _I_CaL is shown truncated. (B) Two sets of superimposed simulations generated for normal and late spontaneous release occurrence (red and blue lines, respectively). When spontaneous release is late, _I_NaCa is relatively small and DD significantly slows (Slow DD). Each set displays simulated traces of _I_NaCa, membrane potential, _V_m, and the phase of spontaneous Ca2+ release, _P_phase(t), as defined by Eq. 3.

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