Physiological intracellular Ca2+ levels (500-600 nM) are sufficient to maximize Ca2+-dependent IKs activation during normal action potentials in rabbit ventricular myocytes.
Key points Ca 2+ i enhanced rabbit ventricular slowly activating delayed rectifier K + current ( I Ks ) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K + current ( I Kr ) amplitude and voltage dependence were unaffected by high Ca 2+ i . When measuring or simulating I Ks during an action potential, I Ks was not different during a physiological Ca 2+ transient or when Ca 2+ i was buffered to 500 n m . Abstract The slowly activating delayed rectifier K + current ( I Ks ) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca 2+ (Ca 2+ i ) and β‐adrenergic receptor (β‐AR) stimulation modulate I Ks amplitude and kinetics, but details of these important I Ks regulators and their interaction are limited. We assessed the Ca 2+ i dependence of I Ks in steady‐state conditions and with dynamically changing membrane potential and Ca 2+ i during an AP. I Ks was recorded from freshly isolated rabbit ventricular myocytes using whole‐cell patch clamp. With intracellular pipette solutions that controlled free Ca 2+ i , we found that raising Ca 2+ i from 100 to 600 n m produced similar increases in I Ks as did β‐AR activation, and the effects appeared additive. Both β‐AR activation and high Ca 2+ i increased maximally activated tail I Ks , negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well‐established mathematical model of the rabbit myocyte. In both AP‐clamp experiments and simulations, I Ks recorded during a normal physiological Ca 2+ transient was similar to I Ks measured with Ca 2+ i clamped at 500–600 n m . Thus, our study provides novel quantitative data as to how physiological Ca 2+ i regulates I Ks amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar Ca 2+ i , in the submembrane or junctional cleft space, is not required to maximize Ca 2+ i ‐dependent I Ks activation during normal Ca 2+ transients. image
Bartos et al. (Sat,) studied this question.
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