Model-free free energy for voltage-gated channels

1 C o m m e n t a r y Models have a habit of clinging to the boot-soles of ion channel biophysicists. Our primary electrophysiological recordings displayed in the Results section almost always presage a Discussion section replete with multi-state schemes: gating models, conduction models, hidden Markov models, straightforward models that enlighten , opaque models that obfuscate, heuristic models with few parameters (oversimplified), complete models with many (overcomplexified) analytically tractable models for algebra lovers, gargantuan models for simulation lovers, models that spew out swarms of rate constants—well, reading the JGP can be exhausting sometimes. In this issue, Chowdury and Chanda introduce an elegant analysis of voltage-dependent channel gating that yields a key parameter, the free energy of channel opening, in a virtually model-free way. Voltage-gated ion channels have kept electrophysiolo-gists off the streets for decades by challenging them with a fundamental and deeply appealing question to chew on: how does membrane voltage, which subjects any charged amino acid in the protein's membrane-embedded core to enormous electric force fields tugging upon it (10 6 V/m), drive transitions between closed and open conformations of these proteins? This question has been attacked for over 60 years with increasingly sophisticated methods and elaborate models of the transmembrane movement of protein-associated charges that accompany pore opening. Because this charge movement is demanded by thermodynamics, it was confidently known to exist in voltage-gated channels long ago, even before its direct detection by Armstrong and Bezanilla (1974). Nowadays, this " gat-ing current " is a readily observable, standard part of the electrophysiologist's toolkit, and high-resolution structures of the charge-bearing voltage-sensitive domains (VSDs) of several K v channels (Jiang et al., 2003; Long et al., 2007; Clayton et al., 2008), and of a putative Na v channel (Payandeh et al., 2011), have enriched the field with physical pictures—themselves food for current controversies—of how gating charge actually moves. Gating current is detected by holding the membrane at a hyperpolarized voltage, where the channels are all closed and the VSDs are all in the " down " position (their charges exposed to the intracellular side of the membrane), and then stepping to a test voltage to observe, typically in the first few hundred microseconds after the voltage change, the transient blip of current that signals the VSD's charged cargo moving outwards to the " up " position. Integrating that blip over time gives the net charge moved at …