Functional Studies of Sodium Channels: From Target to Compound Identification

Abstract

Over the last six decades, voltage-gated sodium (Na ) channels have attracted a great deal of scientific and pharmaceutical interest, driving fundamental advances in both biology and technology. The structure and physiological function of these channels have been extensively studied; clinical and genetic data have uncovered their implication in diseases such as epilepsy, arrhythmias, and pain, bringing them into focus as current and future drug targets. While different techniques have been established to record the activity of Na channels, proper determination of their properties still presents serious challenges, depending upon the experimental conditions and the desired subtype of channel to be characterized. The aim of this unit is to review the characteristics of Na channels, their properties, the cells in which they can be studied, and the currently available techniques. Topics covered include the determination of Na -channel biophysical properties as well as the use of toxins to discriminate between subtypes using electrophysiological or optical methods. Perspectives on the development of high-throughput screening assays with their advantages and limitations are also discussed to allow a better understanding of the challenges encountered in voltage-gated sodium channel preclinical drug discovery. © 2016 by John Wiley & Sons, Inc.

Targeting C-fibers for peripheral acting anti-tussive drugs

“…At the doses studied, however, the drug did not inhibit capsaicin evoked cough all but proving that the drug was not potent enough to effectively block the NaVs in capsaicin-sensitive vagal C-fibers [38]. Fortunately, over the past decade there has been substantive progress made in the development of new NaV blockers that are addressing both the issue of potency (NaV blockers with IC50s in the nanomolar range), and safety [39].…”

Design, synthesis and biological evaluation of N-substituted α-hydroxyimides and 1,2,3-oxathiazolidine-4-one-2,2-dioxides with anticonvulsant activity

“…This state-dependent mechanism in Nav channels is shared with ACDs such as phenytoin, carbamazepine and lamotrigine, among others 32 , 33 . Nav channels are voltage dependent and have at least three well recognized states 34 , 35 . When the cell membrane potential is hyperpolarized, the channel is in the resting closed state, then when the membrane potential rise, the channel turns to an open state and subsequently fall into a not conducting inactive state.…”

Chemical and Biological Tools for the Study of Voltage‐Gated Sodium Channels in Electrogenesis and Nociception

“…As the cell depolarizes, the S4 helices move outward, triggering conformational changes that prompt the opening of the channel pore. [8] Movement of the DIV S4 helix is the last to occur, [9] resulting in a synchronous conformational change in the intracellular loop between DIII and DIV. Within this loop, the position of the isoleucine-phenylalanine-methionine (IFM) particle is altered to inhibit Na + conduction-a process termed fast inactivation, which occurs within milliseconds of channel opening.…”