A compartmentalized mathematical model of mouse atrial myocytes

Abstract

Various experimental mouse models are extensively used to research human diseases, including atrial fibrillation, the most common cardiac rhythm disorder. Despite this, there are no comprehensive mathematical models that describe the complex behavior of the action potential and [Ca²⁺]_i transients in mouse atrial myocytes. Here, we develop a novel compartmentalized mathematical model of mouse atrial myocytes that combines the action potential, [Ca²⁺]_i dynamics, and β-adrenergic signaling cascade for a subpopulation of right atrial myocytes with developed transverse-axial tubule system. The model consists of three compartments related to β-adrenergic signaling (caveolae, extracaveolae, and cytosol) and employs local control of Ca²⁺ release. It also simulates ionic mechanisms of action potential generation and describes atrial-specific Ca²⁺ handling as well as frequency dependences of the action potential and [Ca²⁺]_i transients. The model showed that the T-type Ca²⁺ current significantly affects the later stage of the action potential, with little effect on [Ca²⁺]_i transients. The block of the small-conductance Ca²⁺-activated K⁺ current leads to a prolongation of the action potential at high intracellular Ca²⁺. Simulation results obtained from the atrial model cells were compared with those from ventricular myocytes. The developed model represents a useful tool to study complex electrical properties in the mouse atria and could be applied to enhance the understanding of atrial physiology and arrhythmogenesis.NEW & NOTEWORTHY A new compartmentalized mathematical model of mouse right atrial myocytes was developed. The model simulated action potential and Ca²⁺ dynamics at baseline and after stimulation of the β-adrenergic signaling system. Simulations showed that the T-type Ca²⁺ current markedly prolonged the later stage of atrial action potential repolarization, with a minor effect on [Ca²⁺]_i transients. The small-conductance Ca²⁺-activated K⁺ current block resulted in prolongation of the action potential only at the relatively high intracellular Ca²⁺.

Keywords: Ca2+ dynamics; T-type Ca2+ channels; atrial action potential; small-conductance Ca2+-activated K+ channels; transverse-axial tubular system; β1-adrenergic signaling; β2-adrenergic signaling.