CHAPTER 5: Voltage-gated Sodium Channels: Structure, Function, and Molecular Pharmacology
Published:03 Sep 2014
Special Collection: 2014 ebook collection , 2011-2015 industrial and pharmaceutical chemistry subject collectionSeries: Drug Discovery
Voltage-gated sodium channels initiate action potentials in neurons and other excitable cells, and they are responsible for propagation of action potentials along nerve and muscle fibers. They are complexes of a large pore-forming α-subunit and smaller β-subunits. Multiple genes encode sodium channel subunits, and the distinct sodium channel subtypes have subtle differences in functional properties, differential expression in excitable cells, and differential distribution in subcellular compartments. These differences in function and localization contribute to the specialized functional roles of sodium channels in neuronal physiology and pharmacology. Studies of the structure and function of sodium channels have revealed the molecular basis for voltage-dependent activation, inactivation, and ion conductance and selectivity. Drugs that act on sodium channels are used in local anesthesia and in treatment of cardiac arrhythmias, epilepsy, and bipolar disorder. Current drug discovery efforts are focused on development of sodium channel blockers that would be selective for sodium channels in sensory neurons and would have long-term therapeutic benefit for chronic pain. These functional and pharmacological properties of sodium channels are now being analyzed at the structural level through x-ray crystallographic studies of ancestral bacterial sodium channels. The resulting structures have given new insight into the functional architecture of the sodium channel and its drug receptor sites at the atomic level and have revealed lateral fenestrations that would allow direct access to the local anesthetic receptor site in the pore for entry of drugs from the membrane bilayer.