Calcium and voltage-activated potassium (BK) channels are key actors in cell physiology, both in neuronal and non-neuronal cells and tissues. Through negative feedback between intracellular Ca2+ and membrane voltage, BK channels provide a damping mechanism for excitatory signals. Molecular modulation of these channels by alternative splicing, auxiliary subunits and post-translational modifications showed that these channels are subjected to many mechanisms that add diversity to the BK channel α subunit gene. This complexity of interactions modulates BK channel gating, modifying the energetic barrier of voltage sensor domain activation and channel opening. Regions for voltage as well as Ca2+ sensitivity have been identified, and the crystal structure generated by the 2 RCK domains contained in the C-terminal of the channel has been described. The linkage of these channels to many intracellular metabolites and pathways, as well as their modulation by extracellular natural agents, has been found to be relevant in many physiological processes. This review includes the hallmarks of BK channel biophysics and its physiological impact on specific cells and tissues, highlighting its relationship with auxiliary subunit expression.

Expressed in somatosensory neurons of the dorsal root and trigeminal ganglion, the transient receptor potential melastatin 8 (TRPM8) channel is a Ca2+-permeable cation channel activated by cold, voltage, PIP2 and menthol. Although TRPM8 channel gating has been characterized at the single channel and macroscopic current levels, there is currently no consensus regarding the extent to which temperature and voltage sensors couple to the conduction gate. In the present study we extended the range of voltages at which the TRPM8-induced ionic currents were measured and made careful measurements of the maximum open probability the channel can attain at different temperatures by means of fluctuation analysis. The first direct measurements of TRPM8 channel temperature-driven conformational rearrangements provided here suggest that temperature alone is able to open the channel and that the opening reaction is voltage-independent. Voltage is a partial activator of TRPM8 channels, since absolute open probability values measured with fully activated voltage sensors are less than 1 and they decrease as temperature rises. By unveiling the fast temperature-dependent deactivation process, we show that TRPM8 channel deactivation is well described by a double exponential time course. The fast and slow deactivation processes are temperature-dependent with enthalpy changes of 27.2 kcalmol-1 and 30.8 kcalmol-1. The overall Q10 for the closing reaction is about 33. A three-tiered allosteric model containing four voltage sensors and four temperature sensors can account for the complex deactivation kinetics and coupling between voltage and temperature sensor activation and channel opening.

Significance: H _v 1 proton channels, since their open probability increases with depolarization and low pH, are fundamental in sustaining the suitable pH gradient for cell survival. Here, we have characterized the gating current elicited by the monomeric mutant proton channel N264R with the aim of understanding the voltage-dependent processes that control channel opening. Gating currents precede ion currents, indicating that a large fraction of gating charge is displaced before H _v 1 opening. The voltage sensor displacements are complex and consist of numerous well-defined states. However, most of the charge is displaced in a single transition that probably leads to channel opening. The positively charged arginine in the N264R channel promotes gating charge trapping in addition to blocking the proton currents.

In 1943, David Goldman published a seminal paper in The Journal of General Physiology that reported a concise expression for the membrane current as a function of ion concentrations and voltage. This body of work was, and still is, the theoretical pillar used to interpret the relationship between a cell’s membrane potential and its external and/or internal ionic composition. Here, we describe from an historical perspective the theory underlying the constant-field equation and its application to membrane ion transport.

Significance: Acid extrusion in various types of cells and the reactive oxygen species production by the NADPH oxidase in phagocytes and microglia are mediated by the voltage-gated proton channel (H _v 1). One of the biophysical properties essential for the H _v 1 function is its ΔpH-dependent gating. Here, we measured the H _v 1 gating currents’ pH dependence in the monomeric nonconducting D160N Ciona intestinalis H _v 1 mutant. We demonstrated that H _v 1 ΔpH-dependent gating is a consequence of voltage sensor modulation by direct gating currents recordings. Around 60% of the energy stored in the ΔpH is coupled to the H _v 1 voltage sensor activation. Therefore, the proton chemical energy is transduced to the voltage sensor activation in H _v 1 to produce ΔpH-dependent gating.