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Biochemistry
2010 Jun 15;4923:4804-12. doi: 10.1021/bi100207k.
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μ-conotoxin KIIIA derivatives with divergent affinities versus efficacies in blocking voltage-gated sodium channels.
Zhang MM, Han TS, Olivera BM, Bulaj G, Yoshikami D.
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The possibility of independently manipulating the affinity and efficacy of pore-blocking ligands of sodium channels is of interest for the development of new drugs for the treatment of pain. The analgesic mu-conotoxin KIIIA (KIIIA), a 16-residue peptide with three disulfide bridges, is a pore blocker of voltage-gated sodium channels, including neuronal subtype Na(V)1.2 (K(d) = 5 nM). At saturating concentrations, KIIIA incompletely blocks the sodium current of Na(V)1.2, leaving a 5% residual current (rI(Na)). Lys7 is an important residue: the K7A mutation decreases both the efficacy (i.e., increases rI(Na) to 23%) and the affinity of the peptide (K(d) = 115 nM). In this report, various replacements of residue 7 were examined to determine whether affinity and efficacy were inexorably linked. Because of their facile chemical synthesis, KIIIA analogues that had as a core structure the disulfide-depleted KIIIA[C1A,C2U,C9A,C15U] (where U is selenocysteine) or ddKIIIA were used. Analogues ddKIIIA and ddKIIIA[K7X], where X represents one of nine different amino acids, were tested on voltage-clamped Xenopus oocytes expressing rat Na(V)1.2 or Na(V)1.4. Their affinities ranged from 0.01 to 36 muM and rI(Na) values from 2 to 42%, and these two variables appeared to be uncorrelated. Instead, rI(Na) varied inversely with side chain size, and remarkably charge and hydrophobicity appeared to be inconsequential. The ability to manipulate a mu-conopeptide's affinity and efficacy, as well as its capacity to interfere with subsequent tetrodotoxin binding, greatly expands its scope as a reagent for probing sodium channel structure and function and may also lead to the development of mu-conotoxins as safe analgesics.
Akopian,
The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.
1999, Pubmed
Akopian,
The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.
1999,
Pubmed Amaya,
The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity.
2006,
Pubmed Armishaw,
Alpha-selenoconotoxins, a new class of potent alpha7 neuronal nicotinic receptor antagonists.
2006,
Pubmed
,
Xenbase Billen,
Animal peptides targeting voltage-activated sodium channels.
2008,
Pubmed Brackenbury,
Voltage-gated Na+ channels: potential for beta subunits as therapeutic targets.
2008,
Pubmed Bulaj,
Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels.
2005,
Pubmed Catterall,
International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels.
2005,
Pubmed Catterall,
Inherited neuronal ion channelopathies: new windows on complex neurological diseases.
2008,
Pubmed Cestèle,
Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.
2000,
Pubmed Cruz,
Conus geographus toxins that discriminate between neuronal and muscle sodium channels.
1985,
Pubmed Daly,
Marine toxins and nonmarine toxins: convergence or symbiotic organisms?
2004,
Pubmed Fiedler,
Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels Na(V)1.2, 1.6 and 1.7.
2008,
Pubmed
,
Xenbase French,
Sodium channel toxins--receptor targeting and therapeutic potential.
2004,
Pubmed French,
Interactions between a pore-blocking peptide and the voltage sensor of the sodium channel: an electrostatic approach to channel geometry.
1996,
Pubmed Fry,
The toxicogenomic multiverse: convergent recruitment of proteins into animal venoms.
2009,
Pubmed Gowd,
Site-specific effects of diselenide bridges on the oxidative folding of a cystine knot peptide, omega-selenoconotoxin GVIA.
2010,
Pubmed Han,
Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
2009,
Pubmed
,
Xenbase Han,
Disulfide-Depleted Selenoconopeptides: a Minimalist Strategy to Oxidative Folding of Cysteine-Rich Peptides.
2010,
Pubmed Hui,
Electrostatic and steric contributions to block of the skeletal muscle sodium channel by mu-conotoxin.
2002,
Pubmed Khoo,
Structure of the analgesic mu-conotoxin KIIIA and effects on the structure and function of disulfide deletion.
2009,
Pubmed
,
Xenbase Lattes,
Local infiltration of gonyautoxin is safe and effective in treatment of chronic tension-type headache.
2009,
Pubmed Marcil,
Antinociceptive effects of tetrodotoxin (TTX) in rodents.
2006,
Pubmed Moczydlowski,
Discrimination of muscle and neuronal Na-channel subtypes by binding competition between [3H]saxitoxin and mu-conotoxins.
1986,
Pubmed Muttenthaler,
Solving the alpha-conotoxin folding problem: efficient selenium-directed on-resin generation of more potent and stable nicotinic acetylcholine receptor antagonists.
2010,
Pubmed
,
Xenbase Penzotti,
Differences in saxitoxin and tetrodotoxin binding revealed by mutagenesis of the Na+ channel outer vestibule.
1998,
Pubmed
,
Xenbase Perkins,
Protein volumes and hydration effects. The calculations of partial specific volumes, neutron scattering matchpoints and 280-nm absorption coefficients for proteins and glycoproteins from amino acid sequences.
1986,
Pubmed Rodriguez-Navarro,
Neosaxitoxin as a local anesthetic: preliminary observations from a first human trial.
2007,
Pubmed Santarelli,
A cation-pi interaction discriminates among sodium channels that are either sensitive or resistant to tetrodotoxin block.
2007,
Pubmed
,
Xenbase Sato,
Active site of mu-conotoxin GIIIA, a peptide blocker of muscle sodium channels.
1991,
Pubmed Terlau,
Conus venoms: a rich source of novel ion channel-targeted peptides.
2004,
Pubmed Trimmer,
Regulation of muscle sodium channel transcripts during development and in response to denervation.
1990,
Pubmed
,
Xenbase Walewska,
Integrated oxidative folding of cysteine/selenocysteine containing peptides: improving chemical synthesis of conotoxins.
2009,
Pubmed West,
Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons.
2002,
Pubmed Wood,
Voltage-gated sodium channels and pain pathways.
2004,
Pubmed Yu,
Overview of the voltage-gated sodium channel family.
2003,
Pubmed Zhang,
Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels.
2007,
Pubmed
,
Xenbase Zhang,
Synergistic and antagonistic interactions between tetrodotoxin and mu-conotoxin in blocking voltage-gated sodium channels.
2009,
Pubmed
,
Xenbase
