Mechanisms of drug binding to voltage-gated sodium channels

Abstract

Voltage-gated sodium (Na+) channels are expressed in virtually all electrically excitable tissues and are essential for muscle contraction and the conduction of impulses within the peripheral and central nervous systems. Genetic disorders that disrupt the function of these channels produce an array of Na+ channelopathies resulting in neuronal impairment, chronic pain, neuromuscular pathologies, and cardiac arrhythmias. Because of their importance to the conduction of electrical signals, Na+ channels are the target of a wide variety of local anesthetic, antiarrhythmic, anticonvulsant, and antidepressant drugs. The voltage-gated family of Na+ channels is composed of α-subunits that encode for the voltage sensor domains and the Na+-selective permeation pore. In vivo, Na+ channel α-subunits are associated with one or more accessory β-subunits (β1–β4) that regulate gating properties, trafficking, and cell-surface expression of the channels. The permeation pore of Na+ channels is divided in two parts: the outer mouth of the pore is the site of the ion selectivity filter, while the inner cytoplasmic pore serves as the channel activation gate. The cytoplasmic lining of the permeation pore is formed by the S6 segments that include highly conserved aromatic amino acids important for drug binding. These residues are believed to undergo voltage-dependent conformational changes that alter drug binding as the channels cycle through the closed, open, and inactivated states. The purpose of this chapter is to broadly review the mechanisms of Na+ channel gating and the models used to describe drug binding and Na+ channel inhibition.