Luigi Catacuzzeno

Glioblastoma (GBM), the most lethal form of brain tumors, bases its malignancy on the strong ability of its cells to migrate and invade the narrow spaces of healthy brain parenchyma. Cell migration and invasion are both critically dependent on changes in cell volume and shape driven by the transmembrane transport of osmotically important ions such as K + and Cl − . However, while the Cl − channels participating in cell volume regulation have been clearly identified, the precise nature of the K + channels involved is still uncertain. Using a combination of electrophysiological and imaging approaches in GBM U87‐MG cells, we found that hypotonic‐induced cell swelling triggered the opening of Ca 2+ ‐activated K + (K Ca ) channels of large and intermediate conductance (BK Ca and IK Ca , respectively), both highly expressed in GBM cells. The influx of Ca 2+ mediated by the hypotonic‐induced activation of mechanosensitive channels was found to be a key step for opening both the BK Ca and the IK Ca channels. Finally, the activation of both K Ca channels mediated by mechanosensitive channels was found to be essential for the development of the regulatory volume decrease following hypotonic shock. Taken together, these data indicate that K Ca channels are the main K + channels responsible for the volume regulation in U87‐MG cells.

We celebrate this year the 50th anniversary of the first electrophysiological recordings of the gating currents from voltage-dependent ion channels done in 1973. This retrospective tries to illustrate the context knowledge on channel gating and the impact gating-current recording had then, and how it continued to clarify concepts, elaborate new ideas, and steer the scientific debate in these 50 years. The notion of gating particles and gating currents was first put forward by Hodgkin and Huxley in 1952 as a necessary assumption for interpreting the voltage dependence of the Na and K conductances of the action potential. 20 years later, gating currents were actually recorded, and over the following decades have represented the most direct means of tracing the movement of the gating charges and gaining insights into the mechanisms of channel gating. Most work in the early years was focused on the gating currents from the Na and K channels as found in the squid giant axon. With channel cloning and expression on heterologous systems, other channels as well as voltage-dependent enzymes were investigated. Other approaches were also introduced (cysteine mutagenesis and labeling, site-directed fluorometry, cryo-EM crystallography, and molecular dynamics [MD] modeling) to provide an integrated and coherent view of voltage-dependent gating in biological macromolecules. The layout of this retrospective reflects the past 50 years of investigations on gating currents, first addressing studies done on Na and K channels and then on other voltage-gated channels and non-channel structures. The review closes with a brief overview of how the gating-charge/voltage-sensor movements are translated into pore opening and the pathologies associated with mutations targeting the structures involved with the gating currents.