Computational biology in the study of cardiac ion channels and cell electrophysiology

Abstract

The cardiac cell is a complex biological system where various processes interact to generate electrical excitation (the action potential, AP) and contraction. During AP generation, membrane ion channels interact nonlinearly with dynamically changing ionic concentrations and varying transmembrane voltage, and are subject to regulatory processes. In recent years, a large body of knowledge has accumulated on the molecular structure of cardiac ion channels, their function, and their modification by genetic mutations that are associated with cardiac arrhythmias and sudden death. However, ion channels are typically studied in isolation (in expression systems or isolated membrane patches), away from the physiological environment of the cell where they interact to generate the AP. A major challenge remains the integration of ion-channel properties into the functioning, complex and highly interactive cell system, with the objective to relate molecular-level processes and their modification by disease to whole-cell function and clinical phenotype. In this article we describe how computational biology can be used to achieve such integration. We explain how mathematical (Markov) models of ion-channel kinetics are incorporated into integrated models of cardiac cells to compute the AP. We provide examples of mathematical (computer) simulations of physiological and pathological phenomena, including AP adaptation to changes in heart rate, genetic mutations in SCN5A and HERG genes that are associated with fatal cardiac arrhythmias, and effects of the CaMKII regulatory pathway and β-adrenergic cascade on the cell electrophysiological function. Prologue'Things should be made as simple as possible, but not any simpler.' Albert EinsteinCardiac muscle can generate propagating electrical impulses (action potentials), a property that classifies it as an excitable tissue similar to skeletal muscle and nerve. At the single-cell level, the electrical action potential (AP) triggers mechanical contraction by inducing a transient rise of intracellular calcium which, in turn, carries the contraction message to the contractile proteins of the cell. This process that couples electrical excitation to mechanical function is termed excitation-contraction coupling. APs are generated by individual cells and are conducted from cell to cell through intercellular gap junctions, forming waves of excitation that activate and synchronize the blood pumping action of the heart. Similar to nerve and skeletal muscle, AP initiation and conduction in cardiac ventricular tissue rely mostly on a single membrane process, namely the flow of sodium ions through sodium-specific ion channels. However, unlike the short-duration APs of skeletal muscle and nerve, the cardiac ventricular AP is characterized by long plateau and repolarization phases that prevent premature arrhythmogenic excitation and provide control of mechanical contraction. In NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript contrast to the 'single-current mechanism' of...

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