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.

Although a unifying characteristic common to all transient receptor potential (TRP) channel functions remains elusive, they could be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. TRP channels constitute a large superfamily of ion channels, and can be grouped into seven subfamilies based on their amino acid sequence homology: the canonical or classic TRPs, the vanilloid receptor TRPs, the melastatin or long TRPs, ankyrin (whose only member is the transmembrane protein 1 [TRPA1]), TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins, the polycystins and mucolipins. Because of their role as cellular sensors, polymodal activation and gating properties, many TRP channels are activated by a variety of different stimuli and function as signal integrators. Thus, how TRP channels function and how function relates to given structural determinants contained in the channel-forming protein has attracted the attention of biophysicists as well as molecular and cell biologists. The main purpose of this review is to summarize our present knowledge on the structure of channels of the TRP ion channel family. In the absence of crystal structure information for a complete TRP channel, we will describe important protein domains present in TRP channels, structure–function mutagenesis studies, the few crystal structures available for some TRP channel modules, and the recent determination of some TRP channel structures using electron microscopy.

Significance: In this paper two biological findings are described and explain several muscle changes induced by denervation: ( i ) the sarcolemma of fast myofibers are permeabilized to small molecules such as Evans blue via connexin (Cx) hemichannels and ( ii ) the absence of Cx43/Cx45 hemichannels greatly attenuates the inflammasome activation and muscle atrophy. The first finding explains the activation of proteolysis in denervated muscles. The second demonstrates that muscle inflammation can occur without inflammatory cell infiltration, offering an explanation how denervated muscles can alter other tissues. These findings unveil therapeutic targets to reduce atrophy in diverse clinical conditions. Because Cx hemichannels are permeable to Evans blue, the use of this dye as tracer of cell damage should be reevaluated in different systems.

Temperature sensing is one of the oldest capabilities of living organisms, and is essential for sustaining life, because failure to avoid extreme noxious temperatures can result in tissue damage or death. A subset of members of the transient receptor potential (TRP) ion channel family is finely tuned to detect temperatures ranging from extreme cold to noxious heat, giving rise to thermoTRP channels. Structural and functional experiments have shown that thermoTRP channels are allosteric proteins, containing different domains that sense changes in temperature, among other stimuli, triggering pore opening. Although temperature-dependence is well characterized in thermoTRP channels, the molecular nature of temperature-sensing elements remains unknown. Importantly, thermoTRP channels are involved in pain sensation, related to pathological conditions. Here, we provide an overview of thermoTRP channel activation. We also discuss the structural and functional evidence supporting the existence of an intrinsic temperature sensor in this class of channels, and we explore the basic thermodynamic principles for channel activation. Finally, we give a view of their role in painful pathophysiological conditions.

Calcium- and voltage-activated potassium channels (BK) are regulated by a multiplicity of signals. The prevailing view is that different BK gating mechanisms converge to determine channel opening and that these gating mechanisms are allosterically coupled. In most instances the pore forming α subunit of BK is associated with one of four alternative β subunits that appear to target specific gating mechanisms to regulate the channel activity. In particular, β1 stabilizes the active configuration of the BK voltage sensor having a large effect on BK Ca ²⁺ sensitivity. To determine the extent to which β subunits regulate the BK voltage sensor, we measured gating currents induced by the pore-forming BK α subunit alone and with the different β subunits expressed in Xenopus oocytes (β1, β2IR, β3b, and β4). We found that β1, β2, and β4 stabilize the BK voltage sensor in the active conformation. β3 has no effect on voltage sensor equilibrium. In addition, β4 decreases the apparent number of charges per voltage sensor. The decrease in the charge associated with the voltage sensor in α β4 channels explains most of their biophysical properties. For channels composed of the α subunit alone, gating charge increases slowly with pulse duration as expected if a significant fraction of this charge develops with a time course comparable to that of K ⁺ current activation. In the presence of β1, β2, and β4 this slow component develops in advance of and much more rapidly than ion current activation, suggesting that BK channel opening proceeds in two steps.