Nanopore occlusion: A biophysical mechanism for bipolar cancellation in cell membranes.

Extraordinarily large but short electric field pulses are reported by many experiments to cause bipolar cancellation (BPC). This unusual cell response occurs if a first pulse is followed by a second pulse with opposite polarity. Possibly universal, BPC presently lacks a mechanistic explanation. Multiple versions of the "standard model" of cell electroporation (EP) fail to account for BPC. Here we show, for the first time, how an extension of the standard model can account for a key experimental observation that essentially defines BPC: the amount of a tracer that enters a cell, and how tracer influx can be decreased by the second part of a bipolar pulse. The extended model can also account for the recovery of BPC wherein the extent of BPC is diminished if the spacing between the first and second pulses is increased. Our approach is reverse engineering, meaning that we identify and introduce an additional biophysical mechanism that allows pore transport to change. We hypothesize that occluding molecules from outside the membrane enter or relocate within a pore. Significantly, the additional mechanism is fundamental and general, involving a combination of partitioning and hindrance. Molecules near the membrane can enter pores to block transport of tracer molecules while still passing small ions (charge number ±1) that govern electrical behavior. Our extension of the standard model accounts for key BPC behavior.

Resetting behavior in a model of bursting in secretory pituitary cells: distinguishing plateaus from pseudo-plateaus.

We study a recently discovered class of models for plateau bursting, inspired by models for endocrine pituitary cells. In contrast to classical models for fold-homoclinic (square-wave) bursting, the spikes of the active phase are not supported by limit cycles of the frozen fast subsystem, but are transient oscillations generated by unstable limit cycles emanating from a subcritical Hopf bifurcation around a stable steady state. Experimental time courses are suggestive of such fold-subHopf models because the spikes tend to be small and variable in amplitude; we call this pseudo-plateau bursting. We show here that distinct properties of the response to attempted resets from the silent phase to the active phase provide a clearer, qualitative criterion for choosing between the two classes of models. The fold-homoclinic class is characterized by induced active phases that increase towards the duration of the unperturbed active phase as resets are delivered later in the silent phase. For the fold-subHopf class of pseudo-plateau bursting, resetting is difficult and succeeds only in limited windows of the silent phase but, paradoxically, can dramatically exceed the native active phase duration.