Cell membranes and channel fenestrations

Cell membranes and channel fenestrations refer to the lipid environment and the lateral openings within the transmembrane architecture of voltage-gated ion channels, such as sodium (Nav) and calcium (Cav) channels (Payandeh et al., 2011, Nature). These fenestrations provide a 'hydrophobic pathway' that allows lipid-soluble drug molecules to migrate from the surrounding cell membrane directly into the central cavity of the ion channel pore (Hille, 1977, Journal of General Physiology). This mechanism is distinct from the 'aqueous pathway' where drugs enter through the open intracellular gate, allowing drugs to access their binding sites even when the channel is in a closed or inactivated state. Understanding these structures is crucial for the design of state-dependent blockers used in treating cardiac arrhythmias, epilepsy, and chronic pain, as they determine the kinetics and affinity of drug binding (Gamal El-Din et al., 2018, PNAS). The dimensions and chemical environment of these fenestrations are key determinants of drug potency and selectivity, making them a major focus in pharmacology for modulating electrical signaling in excitable tissues (Catterall & Swanson, 2015, Neuron).

Other names

Lateral fenestrationsHydrophobic access pathwayLipid-exposed poresSide portalsIntramembrane fenestrations

Facilitates the entry of hydrophobic or amphiphilic drug molecules from the lipid bilayer into the central pore of ion channels, bypassing the aqueous gate.