Membrane Potential Bistability in Human Breast Cancer MDA-MB-231 Cells: A “Hodgkin–Huxley Type” Model

Abstract

The plasma membrane voltage ( $V_{\mathrm{m}}$ ) is well known to have significant involvement in a wide range of cellular functions including cancer progression. Voltage imaging revealed that $V_{\mathrm{m}}$ of MDA-MB-231 breast cancer cells is “bistable” with hyperpolarizing voltage transients (HVTs). Here, we formulate a model of $V_{\mathrm{m}}$ incorporating the ion channels $\mathrm{N}{\mathrm{a}}_{\mathrm{v}}1.5$ , $\mathrm{C}{\mathrm{a}}_{\mathrm{v}}3.2$ , and ${\mathrm{K}}_{\mathrm{Ca}}1.1$ . $V_{\mathrm{m}}$ is governed by the Hodgkin–Huxley formalism coupled to intracellular $\mathrm{C}{\mathrm{a}}^{2+}$ dynamics, via $\mathrm{C}{\mathrm{a}}^{2+}$ influx through $\mathrm{C}{\mathrm{a}}_{\mathrm{v}}3.2$ and $\mathrm{C}{\mathrm{a}}^{2+}$ -dependent efflux of ${\mathrm{K}}^{+}$ through ${\mathrm{K}}_{\mathrm{Ca}}1.1$ . Stochastic fluctuations—arising from sparse ion channel expression and $\mathrm{C}{\mathrm{a}}^{2+}$ -induced $\mathrm{C}{\mathrm{a}}^{2+}$ release (CICR)—drive $V_{\mathrm{m}}$ transitions between the otherwise stable depolarized and hyperpolarized states. The model qualitatively reproduces the key experimental observations of HVTs, and their suppression by specific inhibitors of $\mathrm{N}{\mathrm{a}}_{\mathrm{v}}1.5$ or ${\mathrm{K}}_{\mathrm{Ca}}1.1$ . It is predicted that inhibition of CICR should also lead to suppression of HVTs. Our model promises to help the understanding of the dynamic electrical activity of the MDA-MB-231 cell model and its functional consequences, and may inspire future bioelectricity-based cancer diagnosis and therapy.