Molecular Dynamics of the Sodium Channel Pore Vary with Gating: Interactions between P-Segment Motions and Inactivation

摘要: Disulfide trapping studies have revealed that the pore-lining (P) segments of voltage-dependent sodium channels undergo sizable motions on a subsecond time scale. Such pore may be necessary for selective ion translocation. Although traditionally viewed as separable properties, gating and permeation are now known to interact extensively in various classes channels. We investigated interaction μ1 engineered contain two cysteines within P segments. Rates catalyzed internal disulfide formation ( k SS ) were measured K1237C+W1531C mutant expressed oocytes. During repetitive voltage-clamp depolarizations, increasing pulse duration had biphasic effects , which first increased maximum at 200 msec then decreased with longer depolarizations. This result suggested occupancy an intermediate inactivation state I M facilitates motions. Consistent antagonism between alkali metals component slow inactivation, varied inversely external [Na + ] o . examined converse relationship, namely effect flexibility gating, by measuring recovery from Y401C+E758C (YC/EC) Under oxidative conditions, was slower than reduced environment spontaneous YC/EC cross-link is disrupted. The most prominent slowing kinetics, diminution its relative amplitude. conclude segments; conversely, alters inactivation.