Electrophysiology in nanoscale compartments

Voltage-gated ion channels play important roles in many membrane-enclosed structures, including synaptic vesicles, endosomes, mitochondria, chloroplasts, viruses, and bacteria. Here, we study how compartment size and channel gating interact to shape voltage dynamics and ion content in sub-micron structures. In small compartments, assumptions underlying conductance-based (Hodgkin-Huxley type) models of membrane voltage must be relaxed: (1) stochastic gating of individual ion channels can quickly and substantially change membrane voltage; (2) these changes can equilibrate faster than channel state dwell times; and (3) ionic currents, even though as few as two channels, can substantially alter ionic concentrations. We adapted conductance-based models to incorporate these effects, and we then simulated voltage dynamics of small vesicles as a function of vesicle radius and channel density. We identified regimes in this parameter space with qualitatively distinct dynamics. We then performed stochastic simulations to explore the role of NaV1.5 in the maturation of macrophage endosomes. The stochastic model predicted dramatically different dynamics compared with a deterministic approach. Electrophysiology of nanoscale structures can be very different from larger structures, even when ion channel composition and density are preserved.