A New Mechanism of Cellular and Tissue Automaticity

Abstract

Autorhythmicity and synchronization in excitable cells and tissue are intensely debated and linked to distinct mechanistic pathways. Recent studies reveal that inward rectifying potassium channels, implicated in autorhythmicity, are expressed within nanodomain clefts between cardiomyocytes. We hypothesized that dynamic modulation of extracellular potassium concentrations in clefts adjacent to electrically active cells (ephaptic coupling) is a new mechanism governing autorhythmicity in cells and tissue. A fraction of the potassium current (FIK) in the Hodgkin-Huxley model was divided between membrane facing a bulk extracellular space with the other currents, and a cleft volume parameter where extracellular potassium concentration and the reversal potential were tracked for FIK facing the cleft. Bifurcation analysis reveals a range of FIK and cleft volumes that support stable spontaneous oscillations in a single cell. The spontaneous activity is driven by cleft potassium accumulation which transiently raises the potassium reversal potential above the transmembrane potential. Under these conditions, potassium current is inward at the cleft and always outward elsewhere. Under specific FIK values and cleft volumes, inward potassium current in the cleft will cyclically depolarize the cell and trigger an action potential. As FIK increases, the rate of spontaneous activation first increases and then decreases. Increasing cleft volume will dramatically decrease and then gradually increase autorhythmic rates. The addition of diffusion mediated cleft potassium depletion removes the secondary autorhythmic rate increase with larger cleft volumes. In a two-cell model, reduced and heterogeneous FIK, cleft volume, and potassium diffusion can repress or support synchronized automaticity. These data suggest that extracellular nanodomain ionic modulation can facilitate and coordinate individual and coupled cellular autorhythmicity. The results also suggest a new role for fibroblasts, macrophages and/or astrocytes in the modulation of spontaneous oscillatory activity in a variety of electrically active cell networks.