Akimov, S. A. | Search bioRxiv

bioRxiv2025

Photomodulation of Kv Channel Activity

Voltage-gated potassium (Kv) channels shape action potentials, with their activity dependent on anionic lipids and modulated by membrane tension. However, the mechanism by which lipids regulate channel gating is not entirely clear. Cryo-electron microscopy studies suggest that in the down state-- typically associated with the inactive channel--arginines of the voltage sensor interact with lipid phosphates, pulling them upward and locally thinning the membrane by [~]5 [A]. This thinning is absent in the up state of the sensor, which is typically associated with the active channel. To test whether membrane thickness influences gating, we reconstituted Aeropyrum pernix Kv (KvAP) channels into planar lipid bilayers containing photoswitchable lipids. Blue light increased membrane thickness and KvAP activity, while UV light reversed these effects. Our results indicate that membrane thickening disrupts voltage sensor-lipid phosphate interactions, lowering the activation barrier for the up-movement of the voltage sensor and thus, channel opening. The resulting leftward shift in the current-voltage relationship demonstrates a light-driven approach to modulating Kv channel activity, with potential applications in neuronal excitability control. SignificanceVoltage-gated Kv channels respond to membrane voltage in a manner influenced by lipid composition and membrane tension. In the inactive state, voltage-sensing arginines interact with lipid phosphates, and when these interactions are strained--such as by membrane thickening or possibly by membrane tension--less voltage is required for channel opening. We demonstrate this interdependence by showing that a light-triggered increase in membrane thickness reversibly enhances Kv channel activity, directly linking membrane mechanics to voltage sensing. This work also establishes a light-based strategy for spatially precise Kv channel modulation.

biophysics↗

bioRxiv2021

Condensation of the influenza viral fusion peptide alters membrane structure and water permeability

To infect, enveloped viruses employ spike protein, spearheaded by its amphipathic fusion peptide (FP), that upon activation extends out from the viral surface to embed into the target cellular membrane. Here we report that synthesized influenza virus FP are membrane active, generating pores in giant unilamellar vesicles (GUV), and thus potentially explain both influenza virus hemolytic activity and the liposome poration seen in cryo-electron tomography. Experimentally, FP were heterogeneously distributed on the GUV at the time of poration. Consistent with this heterogeneous distribution, molecular dynamics (MD) simulations of asymmetric bilayers with different numbers of FP in one leaflet show FP aggregation. At the center of FP aggregates, a profound change in the membrane structure results in thinning, higher water permeability, and curvature. Ultimately, a hybrid bilayer nanodomain can form with one lipidic leaflet and one peptidic leaflet. Membrane elastic theory predicts a reduced barrier to water pore formation when even a dimer of FP thins the membrane as above, and the FP of that dimer tilts, to continue the leaflet bending initiated by the hydrophobic mismatch between the FP dimer and the surrounding lipid.

biophysics↗