Emergent pacemaking and tissue heterogeneity in a calcium feedback regulatory model of the sinoatrial node.

Abstract

The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN activity emerges at an early point in life, and maintains a steady rhythm for the lifetime of the organism. The ion channel composition and currents of the cells can be influenced by a variety of factors. Therefore, the emergent activity and long-term stability imply some form of dynamical feedback control of the SAN cell activity. Here, we adapt a recent neuronal model to the SAN rabbit cell. The model describes a minimal regulatory mechanism of neuronal ion channel conductance based on a feedback loop defined by an intracellular [Ca2+] level as its target. Briefly, the cell upregulates or downregulates its channel mRNA and membrane expression levels based on the difference between the intercellular Ca2+ level in the cell and a set intercellular Ca2+ target. Based on this feedback model, spontaneous electrical activity emerges in the SAN cell from a quiescent state with low initial conductances. As conductances increase, the intracellular [Ca2+] level reaches the target, and ion channel conductance reach a steady state consistent with sustained spontaneous activity. In a 2D tissue, variability in [Ca2+] target leads to heterogeneous ion channel expression and Ca2+ transients throughout the tissue. Further, dominant focal clusters appear, which interact with one another leading to a heterogeneous tissue cycle length, implying that variability in heart rate is an emergent property of the feedback model. Finally, the 2D tissue is robust to the silencing of leading cells or ion channel knock-outs. Thus, the calcium feedback regulatory model explains a number of experimental data using a minimal description of intracellular calcium and ion channel regulatory networks.