Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels

Abstract

Voltage-gated ion channels (VGICs) are membrane proteins that switch from a closed to open state in response to changes in membrane potential, thus enabling ion fluxes across the cell membranes. The mechanism that regulate the structural rearrangements occurring in VGICs in response to changes in membrane potential still remains one of the most challenging topic of modern biophysics. Na(+), Ca(2+) and K(+) voltage-gated channels are structurally formed by the assembly of four similar domains, each comprising six transmembrane segments. Each domain can be divided into two main regions: the Pore Module (PM) and the Voltage-Sensing Module (VSM). The PM (helices S5 and S6 and intervening linker) is responsible for gate opening and ion selectivity; by contrast, the VSM, comprising the first four transmembrane helices (S1-S4), undergoes the first conformational changes in response to membrane voltage variations. In particular, the S4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing. In neurons, specific gating properties of each channel subtype underlie a variety of biological events, ranging from the generation and propagation of electrical impulses, to the secretion of neurotransmitters and to the regulation of gene expression. Given the important functional role played by the VSM in neuronal VGICs, it is not surprising that various VSM mutations affecting the gating process of these channels are responsible for human diseases, and that compounds acting on the VSM have emerged as important investigational tools with great therapeutic potential. In the present review we will briefly describe the most recent discoveries concerning how the VSM exerts its function, how genetically inherited diseases caused by mutations occurring in the VSM affects gating in VGICs, and how several classes of drugs and toxins selectively target the VSM.

Keywords: channelopathies; gating modifier; ion channels; mutations; voltage-sensing module.

Figure 1

Topological representation of voltage-gated K⁺ (K_v), Na⁺ (Na_v) and Ca²⁺ (Ca_v) channels with related neuronal diseases. Na_v channels are formed by a single polypeptide that contains four domains (I-IV), each with six transmembrane segments (S₁–S₆). β-subunits are single transmembrane proteins that co-assembles with the Na_v α-subunit. Ca_v channels show a similar topology to Na_v channels in their α-subunits, but can be associated with four different auxiliary subunits: the α₂/δ-complex, linked by disulfide bridges, an intracellular β-subunit, and an occasional γ-subunit with four transmembrane segments. Abbreviations: GEFS⁺, Generalized Epilepsy with Febrile Seizures plus; SMEI, Severe Myoclonic Epilepsy of Infancy; FHM1-3, Familial Hemiplegic Migraine type 1-3, respectively; BFNS, Benign Familial Neonatal Seizures; BFNIS, Benign Familial Neonatal-Infantile Seizures; EE, Epileptic Encephalopathy; PE, Primary Erythermalgia; PEPD, Paroxysmal Extreme Pain Disorder; CIP, Congenital Insensitivity to Pain; FEPS2-3, Familial Episodic Pain Syndrome type 2-3, respectively; HSAN7, Hereditary Sensory and Autonomic Neuropathy type 7; EA1-2, Episodic Ataxia type 1-2, respectively; SCA6-13, Spinocerebellar Ataxia type 6-13, respectively; PME, Progressive Myoclonus Epilepsy; CDSRR, Cone Dystrophy with Supernormal Rod Electroretinogram.

Figure 2

Contribution of K⁺ currents during AP firing. Representation of the different K⁺ channel subtypes activated during an AP. The inset shows the effect of K_v7 channel activation during AP firing (modified from Tsantoulas and McMahon, 2014).

Figure 3

Alignment of the VSM of different K_v, Na_v and Ca_v channel subtypes. The VSM have been aligned by using ClustalW2 software; highlighted in yellow are the missense mutations causing EA1 (in K_v1.1); PME (in K_v3.1); SCA13 (in K_v3.3); BFNS (in K_v7.2 and K_v7.3); EEIE7 (in K_v7.2); RCD3B (in K_v8.2); FHM3, SMEI, and GEFS⁺ (in Na_v1.1); and FHM1, EA2 and SCA6 (in Ca_v2.1). Mutations in SCN1A are from a database available at http://www.molgen.ua.ac.be/SCN1AMutations/home/Default.cfm.