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Active Mechanisms Are Needed to Describe Cell Responses to Submicrosecond, Megavolt-per-Meter Pulses: Cell Models for Ultrashort Pulses

Kyle C. Smith ^*  and James C. Weaver ^*

^* Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, and Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts

Correspondence: Address reprint requests to James C. Weaver, E-mail: jcw{at}mit.edu.

Intracellular effects of submicrosecond, megavolt-per-meter pulses imply changes in a cell's plasma membrane (PM) and organelle membranes. The maximum reported PM transmembrane voltage is only 1.6 V and phosphatidylserine is translocated to the outer membrane leaflet of the PM. Passive membrane models involve only displacement currents and predict excessive PM voltages (25 V). Here we use a cell system model with nonconcentric circular PM and organelle membranes to demonstrate fundamental differences between active (nonlinear) and passive (linear) models. We assign active or passive interactions to local membrane regions. The resulting cell system model involves a large number of interconnected local models that individually represent the 1), passive conductive and dielectric properties of aqueous electrolytes and membranes; 2), resting potential source; and 3), asymptotic membrane electroporation model. Systems with passive interactions cannot account for key experimental observations. Our active models exhibit supra-electroporation of the PM and organelle membranes, some key features of the transmembrane voltage, high densities of small pores in the PM and organelle membranes, and a global postpulse perturbation in which cell membranes are depolarized on the timescale of pore lifetimes.