Formulation of Ca²⁺ channel inactivation based on "beta-switch" hypothesis: a simulation study.

Abstract

According to β-switch hypothesis (Findlay 2002), inactivation of I_Ca,L is physiologically dominated by a rapid voltage-dependent process. During β-sympathetic-stimulation, however, this process is replaced by a Ca²⁺-dependent inactivation. Based on his experimental data, we provided two sets of formulation for voltage-dependent inactivation of I_Ca,L (control: steady-state inactivation(f_inf) 0.2 with time constant(τ) 25msec, β-stimulated-state: f_inf=0.55 and τ=500msec at +50mV). They were incorporated into Luo-Rudy model, and our model equipped with Ca²⁺-entry dependent inactivation (Biophys.J.2003), to compare effects on action potentials. Introduction of β-type voltage-inactivation into Luo-Rudy model produced failure of repolarization, in spite of increased Ca²⁺-dependent inactivation due to elevated [Ca²⁺]_i. Repolarization was achieved by the augmented I_Ks, another important factor to modulate action potential duration (APD) during β-stimulation. When I_Ks was doubled in amplitude, however, APD was still highly prolonged. On the other hand, β-type voltage-inactivation could be incorporated into our new model without prominent effects in APDs. This was because Ca²⁺ entered through the channel efficiently produced Ca²⁺-dependent inactivation. Fine-tuning of gating parameters to produce best action potentials, however, was not fully consistent with conditions to simulate voltage-clamp experiments (current decay during square pulses). Further experimental as well as computational studies are required to clarify the highly complicated mechanisms of I_Ca,L inactivation. [Jpn J Physiol 55 Suppl:S125 (2005)]