The Selectivity Filter of the Voltage-gated Sodium Channel Is Involved in Channel Activation

Hilber, Karlheinz; Sandtner, Walter; Kudlacek, Oliver; Glaaser, Ian W.; Weisz, Eva; Kyle, John W.; French, Robert J.; Fozzard, Harry A.; Dudley, Samuel C.; Todt, Hannes

doi:10.1074/jbc.m101933200

Cited by 49 publications

(60 citation statements)

References 80 publications

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“…Furthermore, a mutant -GIIIA (R13Q) has been used to study how the conformation of the pore region near the selectivity filter affects channel dynamics. The data indicate a conformation change in the P-loop of domain IV of Na channels during activation (66).…”

Section: B Na Channel-targeted Toxinsmentioning

confidence: 99%

ConusVenoms: A Rich Source of Novel Ion Channel-Targeted Peptides

Terlau

Olivera

2004

Physiological Reviews

861

828

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Terlau, Heinrich, and Baldomero M. Olivera. Conus Venoms: A Rich Source of Novel Ion Channel-Targeted Peptides. Physiol Rev 84: 41–68, 2004; 10.1152/physrev.00020.2003.—The cone snails (genus Conus) are venomous marine molluscs that use small, structured peptide toxins (conotoxins) for prey capture, defense, and competitor deterrence. Each of the 500 Conus can express ∼100 different conotoxins, with little overlap between species. An overwhelming majority of these peptides are probably targeted selectively to a specific ion channel. Because conotoxins discriminate between closely related subtypes of ion channels, they are widely used as pharmacological agents in ion channel research, and several have direct diagnostic and therapeutic potential. Large conotoxin families can comprise hundreds or thousands of different peptides; most families have a corresponding ion channel family target (i.e., ω-conotoxins and Ca channels, α-conotoxins and nicotinic receptors). Different conotoxin families may have different ligand binding sites on the same ion channel target (i.e., μ-conotoxins and δ-conotoxins to sites 1 and 6 of Na channels, respectively). The individual peptides in a conotoxin family are typically each selectively targeted to a diverse set of different molecular isoforms within the same ion channel family. This review focuses on the targeting specificity of conotoxins and their differential binding to different states of an ion channel.

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Section: B Na Channel-targeted Toxinsmentioning

confidence: 99%

ConusVenoms: A Rich Source of Novel Ion Channel-Targeted Peptides

Terlau

Olivera

2004

Physiological Reviews

861

828

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“…A 10% 13 C sample was used for stereospecific assignment of Leu and Val methyl groups (39). NOE connectivities were obtained with 15 An initial structure of Na V 1.2 CTD was calculated from dihedral angle and NOE distance restraints, with several iterations to resolve ambiguity using ARIA 2.2 (45) and CNS 1.2 (46). The structure was refined with XPLOR-NIH 2.18 using dihedral angle, NOE distance, and residual dipolar coupling constants restraints (47,48).…”

Section: Methodsmentioning

confidence: 99%

Solution Structure of the NaV1.2 C-terminal EF-hand Domain

Miloushev

Levine

Arbing

et al. 2009

Journal of Biological Chemistry

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Voltage-gated sodium channels initiate the rapid upstroke of action potentials in many excitable tissues. Mutations within intracellular C-terminal sequences of specific channels underlie a diverse set of channelopathies, including cardiac arrhythmias and epilepsy syndromes. The three-dimensional structure of the C-terminal residues 1777-1882 of the human Na V 1.2 voltagegated sodium channel has been determined in solution by NMR spectroscopy at pH 7.4 and 290.5 K. The ordered structure extends from residues Leu-1790 to Glu-1868 and is composed of four ␣-helices separated by two short anti-parallel ␤-strands; a less well defined helical region extends from residue Ser-1869 to Arg-1882, and a disordered N-terminal region encompasses residues 1777-1789. Although the structure has the overall architecture of a paired EF-hand domain, the Na V 1. 2؉ titration also were performed for the Na V 1.5 (1773-1878) isoform, demonstrating similar secondary structure architecture and the absence of Ca 2؉ binding by the EFhand loops. Clinically significant mutations identified in the C-terminal region of Na V 1 sodium channels cluster in the helix I-IV interface and the helix II-III interhelical segment or in helices III and IV of the Na V 1.2 (1777-1882) structure.Voltage-gated sodium channels (VGSCs) 5 are molecular assemblies that span the plasma membrane of excitable cells and conduct sodium current selectively in response to depolarizing stimuli. Mutations in VGSCs underlie a variety of diseases, including the cardiac arrhythmogenic Long-QT3 and Brugada syndromes (1, 2) and neurological syndromes, such as epilepsy (3, 4).Known components of VGSCs include a pore-forming ␣ subunit, auxiliary ␤ subunits, and associated modulating proteins, such as calmodulin (5, 6). The ␣ subunit is composed of four homologous six-transmembrane helical domains connected by inter-domain linkers and N-terminal and C-terminal cytoplasmic regions. Specific ␣ subunit isoforms are expressed differentially in skeletal muscle (Na V 1.4), cardiac muscle (Na V 1.5) and the nervous system (Na V 1.1, Na V 1.2, Na V 1.3, splice variants of Na V 1.5, and Na V 1.6-Na V 1.9) and control the rapid upstroke of action potentials (7). VGSC activity is characterized by two open states and several inactivated states (8). Kinetics of channel inactivation occur on timescales ranging from milliseconds to seconds and determine multiple aspects of action potentials (9, 10). The molecular mechanisms of VGSC inactivation are complex and involve the ␣ subunit, the ␤ subunits, and calmodulin (11-13). Specific contributions to ␣ subunit inactivation have been localized to interhelical intra-domain regions (14 -16), the linker region between domains III-IV, which forms the pore occluding inactivation gate (17,18), and the C-terminal cytoplasmic domain (CTD) (19 -21).Specific disease-causing mutations within the CTD affect channel function by altering kinetics of channel inactivation (22). The CTD is predicted by sequence analysis (23, 24) and homology modeling (25-27) to c...

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“…1 at 60 min). Studying current amplitude when holding at Ϫ110 mV is complicated by an initial increase in current amplitude due to relief of slow inactivation (17,34,40), which is later followed by a decrease in amplitude (Fig. 1).…”

Section: Role Of Elevation Of Intracellular Camentioning

confidence: 99%