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+, Ca2+ 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.
Highlights
Voltage-dependent changes in ion fluxes are critical for the generation and propagation of electric signals in and between excitable cells
These studies first established the biophysical basis of voltage-sensing in Voltage-gated ion channels (VGICs), a major breakthrough allowing to translate into molecular clues such theoretical background was the cloning and sequencing of the first VGIC, namely the voltage-gated Na+ channel (VGNC) from the electroplax of Electrophorus electricus (Noda et al, 1984), followed by the cloning of the first voltage-gated Ca2+ channel (VGCC) from rabbit skeletal muscle (Tanabe et al, 1987), and of a voltagegated K+ channel (VGKC) from Drosophila (Papazian et al, 1987)
The general principles of voltage-sensing have been described by purely functional experiments well over 50 years ago, recent progress in apparently distinct fields of investigation ranging from molecular genetics to X-ray crystallography have contributed to the identification of human diseases caused by altered gating of a large number of VGICs, and to the description of the intimate molecular mechanisms of this process at nearly atomic level resolution
Summary
Voltage-dependent changes in ion fluxes are critical for the generation and propagation of electric signals in and between excitable cells. The VSM of each domain senses the membrane potential variations, switching from a resting to an activated configuration, a necessary prerequisite for subsequent pore opening; the S1–S4 transmembrane segments play a crucial role in this process Both in VGKCs (Long et al, 2007) as well as in bacterial VGNCs (Payandeh et al, 2011), the VSM of each domain interacts with the PM of a neighboring domain, allowing movements of the VSM module to be directly translated into conformational changes of the PM. Structural information regarding the molecular mechanisms of ion permeation, selectivity, and pore opening/closing were obtained from the crystal structure of bacterial ‘‘inward rectifier’’ K+ channels (KIR) KcsA (Doyle et al, 1998), MthK (Jiang et al, 2002a,b), and KirBac1.1 (Kuo et al, 2003), whose membrane core only contains the regions corresponding to the S5–S6 module. In hyperpolarization-activated cyclic nucleotide gated channels (HCN) decoupling between VSM and PM triggers pore closure (Blunck and Batulan, 2012)
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