CNS & Neurological Disorders - Drug Targets, 2008, 7, 000-000 1 1871-5273/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Voltage-Gated Sodium Channels in Neurological Disorders Mohamed Chahine *,1 , Aurélien Chatelier 1 , Olga Babich 2 and Johannes J. Krupp 2 1 Le Centre de recherches Université Laval Robert-Griffard, and Department of Medicine, Laval University, Quebec City, Quebec, Canada 2 AstraZeneca R&D Södertälje, Molecular Pharmacology Department, Södertälje, Sweden Abstract: Voltage-gated sodium channels play an essential biophysical role on many excitable cells such as neurons. They transmit electrical signals through action potential (AP) generation and propagation in the peripheral (PNS) and cen- tral nervous systems (CNS). Each sodium channel is formed by one -subunit and one or more -subunits. There is grow- ing evidence indicating that mutations, changes in expression, or inappropriate modulation of these channels can lead to electrical instability of the cell membrane and inappropriate spontaneous activity observed during pathological states. This review describes the biochemical, biophysical and pharmacological properties of neuronal voltage-gated sodium channels (VGSC) and their implication in several neurological disorders. Keywords: Neuronal excitability, action potential, splice variants, channelopathies, expression, toxins, local anesthetics, subunit specific blockers. INTRODUCTION The central nervous system (CNS) is the main compo- nent of the nervous system and is composed of the brain and the spinal cord. Information is transmitted along axons by action potentials (APs) caused by variations in membrane potentials. In most neurons the upstroke of such an AP is generated by a sodium conductance. It was Hodgkin and Huxley who not only recognized the importance of this so- dium channel conductance for the upstroke of the neuronal AP, but also provided algorithms to describe the ionic basis of nerve excitability in the 1950’s, postulating distinct, inde- pendent molecular identities for sodium and potassium con- ductances [1,2]. This hypothesis was directly confirmed by Sakmann and Neher in the 1970’s when they recorded the first single channel elementary currents using the patch- clamp technique [3,4]. The field of ion channel research took another giant step forward with the crystallization of several ion channels, pioneered by MacKinnon in the late 1990’s [5,6]. Today, the notion that the sodium channel conductance in neuronal cells is due to the opening and closing of indi- vidual molecular protein complexes, voltage-gated sodium channels (VGSC), is accepted within the scientific commu- nity. VGSC play a critical role in electrical signaling in the nervous system and are responsible for the initiation and propagation of APs. To fulfill such a function it is essential that VGSC enter first conducting and then non-conducting states rapidly (on a sub-ms to ms timescale) after an appro- priate membrane depolarization. Recently, a number of mu- tations in VGSCs that often result in alterations of this rapid channel gating have been identified and linked to human diseases. Such channelopathies cause periodic paralysis, myotonia, long QT syndrome and other cardiac conductance *Address correspondence to this author at the AstraZeneca R&D Södertälje, Building 209, 15185 Södertälje, Sweden; Tel: +46 8 553 21686; Fax: +46 8 553 25440; E-mail: johannes.krupp@astrazeneca.com disturbances, pain, and epilepsy. Considering these crucial physiological and pathological implications, it is not surpris- ing that VGSC have been, and still are, key targets for drug discovery efforts by the pharmaceutical industry. This re- view focuses on this important class of ion channels, their involvement in neuronal disorders, and recent trends in the development of VGSC compounds for treatment of such disorders. STRUCTURE AND FUNCTION OF VOLTAGE- GATED SODIUM CHANNELS VGSCs are composed of one -subunit, that forms the core of the channel and is responsible for voltage-dependent gating and ion permeation, and several auxiliary -subunits (Fig. 1) [7-9]. Whereas the -subunits are rather small proteins (22-36 kDa) that span the cell membrane only once, the -subunits are large proteins (~260 kDa) composed of four homologous domains (DI–DIV), with each domain containing six - helical transmembrane-spanning segments (S1-S6). The S4 segments of each domain contain several polar amino acid residues that are part of the voltage sensor domain and are crucial for channel gating [10-12]. The short linkers connect- ing the S5 and S6 segments contain a short and nonhelical segment known as the P-segment. The four P-segments of an -subunit create the external mouth of the pore as well as the narrowest part of the ion pathway, the selectivity filter [13- 15]. The cytoplasmic loops connecting the four domains of VGSC have distinct functions. The large intracellular loop connecting homologous domains I and II possesses several shared protein kinase A (PKA), protein kinase C (PKC), and p38 mitogen-activated protein kinase (MAPK) phosphoryla- tion sites and is therefore important in modulating sodium channels [16-19]. This region also interacts with A kinase anchoring protein 15 (AKAP15). AKAP15 enables rapid VGSC modulation by PKA [20]. Other proteins such as syn- aptotagmin can also interact with this loop [21]. The