The Journal of Physical Chemistry B published “From Flux to Function: Extracting Mechanistic Insights from Ion Channels via I–V and I–μ Analyses” by Hannah Weckel-Dahman, Ryan Carlsen, Alexander Daum, and Jessica M. J. Swanson
The molecular origins of ion-channel current–voltage (I–V) relationships are often unclear, obscured by ensemble averaging in experimental analysis and persistent underestimation of single-channel ion currents in simulations. Here, we present a mathematical framework that relates ion channel properties to experimentally measured I–V and current–chemical potential (I–μ) relationships. By accounting for how rates change in response to electrochemical conditions in a multistate kinetic model of systems with sequential binding sites, this approach demonstrates how the spatial arrangement of sites and transition states, together with rate asymmetries in ion uptake, transfer, and release, manifest in distinct open-channel current and conductance profiles. Varying these properties in model systems reveals a molecular basis for understanding rectification and nonohmic open-channel flux. Application to models fit to experimental I–V curves demonstrates that these mechanistic trends hold in heterogeneous systems, suggesting a (potentially) transferable paradigm for open-channel flux in channels and transporters with two or more sequential binding sites. Together, these results establish a theoretical framework for open-channel current and foundation for mechanistically interpreting experimental I–V and I–μ assays.
Professor Swanson wrote”Every nerve impulse, heartbeat, and muscle contraction depends on the coordination of various ion channels that choreograph the movement of charged species across the cell membrane. Scientists have recorded the tiny electrical currents these channels generate, but turning those signals into a clear, mechanistic picture of how ions move across the membrane has remained a longstanding scientific puzzle. Our recent work, published in Phys Chem B, presents a quantitative means to begin bridging the gap between experimentally recorded electrophysiology data and the mechanisms by which proteins move ions under changing cellular conditions. Critically, this work demonstrates that subtle changes in protein architecture, such as shifts in binding-site positions, the voltage sensitivity of each binding site or the relative energies of different translocation events, leave a detectable fingerprint in the current. This means that current-voltage relationships and the relationship between current and chemical gradients can be used not only to describe channel behavior but also to infer the underlying mechanisms. By enabling researchers to map function back onto structure, the mathematical model presented could sharpen our understanding of ion channel physiology and guide the design of drugs that target these essential proteins.”
Learn more about Professor Jessica M. J. Swanson and the Swanson Research Group here.
March 25, 2025