Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Molecular requirements for recognition of brain voltage-gated sodium channels by scorpion alpha-toxins.
Kahn R
,
Karbat I
,
Ilan N
,
Cohen L
,
Sokolov S
,
Catterall WA
,
Gordon D
,
Gurevitz M
.
???displayArticle.abstract???
The scorpion alpha-toxin Lqh2 (from Leiurus quinquestriatus hebraeus) is active at various mammalian voltage-gated sodium channels (Na(v)s) and is inactive at insect Na(v)s. To resolve the molecular basis of this preference we used the following strategy: 1) Lqh2 was expressed in recombinant form and key residues important for activity at the rat brain channel rNa(v)1.2a were identified by mutagenesis. These residues form a bipartite functional surface made of a conserved "core domain" (residues of the loops connecting the secondary structure elements of the molecule core), and a variable "NC domain" (five-residue turn and the C-tail) as was reported for other scorpion alpha-toxins. 2) The functional role of the two domains was validated by their stepwise construction on the similar scaffold of the anti-insect toxin LqhalphaIT. Analysis of the activity of the intermediate constructs highlighted the critical role of Phe(15) of the core domain in toxin potency at rNa(v)1.2a, and has suggested that the shape of the NC-domain is important for toxin efficacy. 3) Based on these findings and by comparison with other scorpion alpha-toxins we were able to eliminate the activity of Lqh2 at rNa(v)1.4 (skeletal muscle), hNa(v)1.5 (cardiac), and rNa(v)1.6 channels, with no hindrance of its activity at Na(v)1.1-1.3. These results suggest that by employing a similar approach the design of further target-selective sodium channel modifiers is imminent.
Alami,
Characterization of Amm VIII from Androctonus mauretanicus mauretanicus: a new scorpion toxin that discriminates between neuronal and skeletal sodium channels.
2003, Pubmed,
Xenbase
Alami,
Characterization of Amm VIII from Androctonus mauretanicus mauretanicus: a new scorpion toxin that discriminates between neuronal and skeletal sodium channels.
2003,
Pubmed
,
Xenbase
Auld,
A neutral amino acid change in segment IIS4 dramatically alters the gating properties of the voltage-dependent sodium channel.
1990,
Pubmed
,
Xenbase
Campos,
Alpha-scorpion toxin impairs a conformational change that leads to fast inactivation of muscle sodium channels.
2008,
Pubmed
,
Xenbase
Cannon,
Pathomechanisms in channelopathies of skeletal muscle and brain.
2006,
Pubmed
Catterall,
Sea anemone toxin and scorpion toxin share a common receptor site associated with the action potential sodium ionophore.
1978,
Pubmed
Catterall,
Neurotoxin binding to receptor sites associated with voltage-sensitive sodium channels in intact, lysed, and detergent-solubilized brain membranes.
1979,
Pubmed
Catterall,
From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.
2000,
Pubmed
Cestèle,
Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.
2000,
Pubmed
Chen,
Differential sensitivity of sodium channels from the central and peripheral nervous system to the scorpion toxins Lqh-2 and Lqh-3.
2002,
Pubmed
Chen,
Interaction of scorpion alpha-toxins with cardiac sodium channels: binding properties and enhancement of slow inactivation.
2001,
Pubmed
Chen,
Modulation of cloned skeletal muscle sodium channels by the scorpion toxins Lqh II, Lqh III, and Lqh alphaIT.
2000,
Pubmed
Clare,
Voltage-gated sodium channels as therapeutic targets.
2000,
Pubmed
Cohen,
Common features in the functional surface of scorpion beta-toxins and elements that confer specificity for insect and mammalian voltage-gated sodium channels.
2005,
Pubmed
Darbon,
Alpha-scorpion neurotoxin derivatives suitable as potential markers of sodium channels. Preparation and characterization.
1983,
Pubmed
el Ayeb,
Differential effects of defined chemical modifications on antigenic and pharmacological activities of scorpion alpha and beta toxins.
1986,
Pubmed
Fontecilla-Camps,
Orthorhombic crystals and three-dimensional structure of the potent toxin II from the scorpion Androctonus australis Hector.
1988,
Pubmed
Gilles,
Scorpion alpha and alpha-like toxins differentially interact with sodium channels in mammalian CNS and periphery.
2000,
Pubmed
Gilles,
Effect of depolarization on binding kinetics of scorpion alpha-toxin highlights conformational changes of rat brain sodium channels.
2001,
Pubmed
Goldin,
Diversity of mammalian voltage-gated sodium channels.
1999,
Pubmed
Gordon,
The selectivity of scorpion alpha-toxins for sodium channel subtypes is determined by subtle variations at the interacting surface.
2003,
Pubmed
Gordon,
The differential preference of scorpion alpha-toxins for insect or mammalian sodium channels: implications for improved insect control.
2007,
Pubmed
Guan,
Structural mechanism governing cis and trans isomeric states and an intramolecular switch for cis/trans isomerization of a non-proline peptide bond observed in crystal structures of scorpion toxins.
2004,
Pubmed
Gurevitz,
The insecticidal potential of scorpion beta-toxins.
2007,
Pubmed
He,
Crystal structures of two alpha-like scorpion toxins: non-proline cis peptide bonds and implications for new binding site selectivity on the sodium channel.
1999,
Pubmed
Housset,
Crystal structure of toxin II from the scorpion Androctonus australis Hector refined at 1.3 A resolution.
1994,
Pubmed
Joho,
Toxin and kinetic profile of rat brain type III sodium channels expressed in Xenopus oocytes.
1990,
Pubmed
,
Xenbase
Karbat,
The unique pharmacology of the scorpion alpha-like toxin Lqh3 is associated with its flexible C-tail.
2007,
Pubmed
Karbat,
Molecular basis of the high insecticidal potency of scorpion alpha-toxins.
2004,
Pubmed
Keynes,
Kinetic analysis of the sodium gating current in the squid giant axon.
1990,
Pubmed
Legros,
Expression of the standard scorpion alpha-toxin AaH II and AaH II mutants leading to the identification of some key bioactive elements.
2005,
Pubmed
Lehmann-Horn,
Voltage-gated ion channels and hereditary disease.
1999,
Pubmed
Little,
delta-Atracotoxins from australian funnel-web spiders compete with scorpion alpha-toxin binding but differentially modulate alkaloid toxin activation of voltage-gated sodium channels.
1998,
Pubmed
Liu,
Molecular basis of the mammalian potency of the scorpion alpha-like toxin, BmK M1.
2005,
Pubmed
,
Xenbase
Rogers,
Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit.
1996,
Pubmed
Sautière,
New toxins acting on sodium channels from the scorpion Leiurus quinquestriatus hebraeus suggest a clue to mammalian vs insect selectivity.
1998,
Pubmed
Scalmani,
Effects in neocortical neurons of mutations of the Na(v)1.2 Na+ channel causing benign familial neonatal-infantile seizures.
2006,
Pubmed
Schnur,
NMR analysis of interaction of LqhalphaIT scorpion toxin with a peptide corresponding to the D4/S3-S4 loop of insect para voltage-gated sodium channel.
2008,
Pubmed
,
Xenbase
Sheets,
The Na channel voltage sensor associated with inactivation is localized to the external charged residues of domain IV, S4.
1999,
Pubmed
Shichor,
Domain 2 of Drosophila para voltage-gated sodium channel confers insect properties to a rat brain channel.
2002,
Pubmed
,
Xenbase
Tejedor,
Photoaffinity labeling of the receptor site for alpha-scorpion toxins on purified and reconstituted sodium channels by a new toxin derivative.
1990,
Pubmed
Thomsen,
Localization of the receptor site for alpha-scorpion toxins by antibody mapping: implications for sodium channel topology.
1989,
Pubmed
Tugarinov,
Solution structures of a highly insecticidal recombinant scorpion alpha-toxin and a mutant with increased activity.
1997,
Pubmed
Wallner,
Modulation of the skeletal muscle sodium channel alpha-subunit by the beta 1-subunit.
1993,
Pubmed
,
Xenbase
Wang,
Exploration of the functional site of a scorpion alpha-like toxin by site-directed mutagenesis.
2003,
Pubmed
Waxman,
Transcriptional channelopathies: an emerging class of disorders.
2001,
Pubmed
Whitaker,
Comparative distribution of voltage-gated sodium channel proteins in human brain.
2001,
Pubmed
Yang,
The position of the fourth segment of domain 4 determines status of the inactivation gate in Na+ channels.
2003,
Pubmed
,
Xenbase
Ye,
Structural basis for the voltage-gated Na+ channel selectivity of the scorpion alpha-like toxin BmK M1.
2005,
Pubmed
,
Xenbase
Zilberberg,
Identification of structural elements of a scorpion alpha-neurotoxin important for receptor site recognition.
1997,
Pubmed
