Sodium Channel Inactivation: Molecular Determinants and Modulation

Abstract

Voltage-gated sodium channels open (activate) when the membrane is depolarized and close on repolarization (deactivate) but also on continuing depolarization by a process termed inactivation, which leaves the channel refractory, i.e., unable to open again for a period of time. In the "classical" fast inactivation, this time is of the millisecond range, but it can last much longer (up to seconds) in a different slow type of inactivation. These two types of inactivation have different mechanisms located in different parts of the channel molecule: the fast inactivation at the cytoplasmic pore opening which can be closed by a hinged lid, the slow inactivation in other parts involving conformational changes of the pore. Fast inactivation is highly vulnerable and affected by many chemical agents, toxins, and proteolytic enzymes but also by the presence of beta-subunits of the channel molecule. Systematic studies of these modulating factors and of the effects of point mutations (experimental and in hereditary diseases) in the channel molecule have yielded a fairly consistent picture of the molecular background of fast inactivation, which for the slow inactivation is still lacking.

Nonfunctional Na V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

“…The gating modifications were consistent with modifications of the kinetics and destabilization of both the inactivated and, to a lesser extent, the activated state. L1649Q is localized in the S4 transmembrane segment of domain IV, a voltage sensor that is particularly important for activation-inactivation coupling (28), consistently with the large effects on inactivation that we have observed. A destabilization of fast inactivation is consistent with a dialysis-resistant I NaP component representing an intrinsic property of the mutant that does not require diffusible modulatory factors.…”

Nav1.4 Deregulation in Dystrophic Skeletal Muscle Leads to Na+Overload and Enhanced Cell Death

“…While values obtained for control fi bers corresponded to those reported ( Ulbricht, 2005 ), the i ' s of mdx 5cv fi bers were ‫ف‬ 1.5 times larger ( Fig. 3 B , bottom).…”

Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes

“…Here, we found that between the fast and slow inactivation, bupivacaine preferably acted on the latter, for which the voltage-dependency and time constants were substantially changed. This finding is in agreement with the fact that the slow inactivation is thought to be accompanied by rearrangement of the channel pore in DIV [26] . use of the S(-)-enantiomer to reduce cardiac toxicity [11] .…”