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. 2009 May 6;96(9):3862-72.
doi: 10.1016/j.bpj.2009.02.017.

Mechanisms of beta-adrenergic modulation of I(Ks) in the guinea-pig ventricle: insights from experimental and model-based analysis

Stefano Severi  1 , Cristiana Corsi, Marcella Rocchetti, Antonio Zaza
Affiliations

Mechanisms of beta-adrenergic modulation of I(Ks) in the guinea-pig ventricle: insights from experimental and model-based analysis

Stefano Severi et al. Biophys J. .

Abstract

Detailed understanding of I(Ks) gating complexity may provide clues regarding the mechanisms of repolarization instability and the resulting arrhythmias. We developed and tested a kinetic model to interpret physiologically relevant I(Ks) properties, including pause-dependence and modulation by beta-adrenergic receptors (beta-AR). I(Ks) gating was evaluated in guinea-pig ventricular myocytes at 36 degrees C in control and during beta-AR stimulation (0.1 micromol/L isoprenaline (ISO)). We tested voltage dependence of steady-state conductance (Gss), voltage dependence of activation and deactivation time constants (tau(act), tau(deact)), and pause-dependence of tau(act) during repetitive activations (tau(react)). The I(Ks) model was developed from the Silva and Rudy formulation. Parameters were optimized on control and ISO experimental data, respectively. ISO strongly increased Gss and its voltage dependence, changed the voltage dependence of tau(act) and tau(deact), and modified the pause-dependence of tau(react). A single set of model parameters reproduced all experimental data in control. Modification of only three transition rates led to a second set of parameters suitable to fit all ISO data. Channel unitary conductance and density were unchanged in the model, thus implying increased open probability as the mechanism of ISO-induced Gss enhancement. The new I(Ks) model was applied to analyze ISO effect on repolarization rate-dependence. I(Ks) kinetics and its beta-AR modulation were entirely reproduced by a single Markov chain of transitions (for each channel monomer). Model-based analysis suggests that complete opening of I(Ks) channels within a physiological range of potentials requires concomitant beta-AR stimulation. Transient redistribution of state occupancy, in addition to direct modulation of transition rates, may underlie beta-AR modulation of I(Ks) time dependence.

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Figures

Figure 1
Figure 1
ISO effect on voltage dependence of IKs gating. Experimental data (mean ± SE) shown by symbols (control: open symbols; ISO: solid symbols); model simulations by lines (control: thin lines; ISO: thick lines). (A) Steady-state activation (n = 15). (B) Extension of steady-state activation simulations over a wider range of potentials (experimental data points as in A superimposed for comparison); dotted lines represent Boltzmann fitting of simulated data. (C) Activation kinetics (n = 15); (D) Deactivation kinetics (n = 16). Voltage protocols in inset.
Figure 2
Figure 2
ISO effect on IKs reactivation kinetics and its pause-dependence (restitution, n = 5). Reactivation time constants (τreact) are plotted versus S1–S2 intervals. Meaning of symbols and lines as in Fig. 1. Experimental data points from Rocchetti et al. (8).
Figure 3
Figure 3
Changes in the voltage dependence of model transition rates (see schematic on the right) required to model ISO effects. (A) Zone 2 forward (α) and backward (β) transition rates. (B) Opening (θ) and closing (η) transition rates. Thin lines for control conditions; thick lines for ISO. Transitions rates unaffected by ISO not shown for simplicity.
Figure 4
Figure 4
Steady-state distribution of model states occupancy at selected potentials. (A) −80 mV = diastolic. (B) 0 mV. (C) +20 mV ≅ 50% activation. (D) +50 mV ≅ 95% activation in control (open bars) and in ISO (solid bars). States (see schematic on the right) are represented on the abscissa from those farther (Zone 2) to those closer (Zone 1) to channel opening (open). State occupancy is defined as (n of channels in a state)/(total n of channels).
Figure 5
Figure 5
Model analysis of IKs activation course during a V-step protocol (inset) in control (thin lines) and in ISO (thick lines). (A) Zone 2 occupancy. (B) Zone 1 occupancy. (C) Open-state occupancy.
Figure 6
Figure 6
Model analysis of IKs deactivation course during a V-step protocol (inset) in control (thin lines) and in ISO (thick lines). Panels as in Fig. 5.
Figure 7
Figure 7
Model analysis of IKs reactivation at a short S1–S2 interval (100 ms) in control (thin line) and in ISO (thick line). Voltage protocols in inset. The dashed line shows the effect of ISO applied after S1 (“ISO step” in inset). (A) Current (IKs). (B) Zone 2 occupancy. (C) Zone 1 occupancy. (D) Open-state occupancy.
Figure 8
Figure 8
Model analysis of IKs reactivation at a long S1–S2 interval (500 ms). Protocol and legends as in Fig. 7.
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References

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