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Voltage-gated sodium channels (VGSCs) are important for action potentials. There are seven major isoforms of the pore-forming and gate-bearing α-subunit (Na(V)1) of VGSCs in mammalian neurons, and a given neuron can express more than one isoform. Five of the neuronal isoforms, Na(V)1.1, 1.2, 1.3, 1.6, and 1.7, are exquisitely sensitive to tetrodotoxin(More)
Peptide neurotoxins from cone snails continue to supply compounds with therapeutic potential. Although several analgesic conotoxins have already reached human clinical trials, a continuing need exists for the discovery and development of novel non-opioid analgesics, such as subtype-selective sodium channel blockers. Micro-conotoxin KIIIA is representative(More)
MuO-conotoxin MrVIB is a blocker of voltage-gated sodium channels, including TTX-sensitive and -resistant subtypes. A comprehensive characterization of this peptide has been hampered by the lack of sufficient synthetic material. Here, we describe the successful chemical synthesis and oxidative folding of MrVIB that has made an investigation of the(More)
mu-Conotoxins are peptides that block sodium channels. Molecular cloning was used to identify four novel mu-conotoxins: CnIIIA, CnIIIB, CIIIA, and MIIIA from Conus consors, C. catus and C. magus. A comparison of their sequences with those of previously characterized mu-conotoxins suggested that the new mu-conotoxins were likely to target(More)
Voltage-gated sodium channels (VGSCs) consist of a pore-forming α-subunit and regulatory β-subunits. Several families of neuroactive peptides of Conus snails target VGSCs, including μO-conotoxins and μ-conotoxins. Unlike μ-conotoxins and the guanidinium alkaloid saxitoxin (STX), which are pore blockers, μO-conotoxins MrVIA and MrVIB inhibit VGSCs by(More)
The peptides isolated from venoms of predatory marine Conus snails ("conotoxins") are well-known to be highly potent and selective pharmacological agents for voltage-gated ion channels and receptors. We report the discovery of two novel TTX-resistant sodium channel blockers, mu-conotoxins SIIIA and KIIIA, from two species of cone snails. The two toxins were(More)
Three new polyhydroxysterols, named muriflasteroids A-C (1-3) were isolated from the South China Sea gorgonian Muriceopsis flavida, together with sixteen known analogs, cholest-3β,5α,6β-triol,3β-acetate (4), 5α-methoxycholest-3β,6β-diol (5), (22E)-cholest-22-en-3β,5α,6β-triol (6), cholest-3β,5α,6β-triol (7), (22E)-24-norcholest-22-en-3β,5α,6β-triol (8),(More)
Described herein is a general approach to identify novel compounds using the biodiversity of a megadiverse group of animals; specifically, the phylogenetic lineage of the venomous gastropods that belong to the genus Conus ("cone snails"). Cone snail biodiversity was exploited to identify three new mu-conotoxins, BuIIIA, BuIIIB and BuIIIC, encoded by the(More)
The excitotoxic conopeptide iota-RXIA induces repetitive action potentials in frog motor axons and seizures upon intracranial injection into mice. We recently discovered that iota-RXIA shifts the voltage-dependence of activation of voltage-gated sodium channel Na(V)1.6 to a more hyperpolarized level. Here, we performed voltage-clamp experiments to examine(More)
BACKGROUND AND PURPOSE Voltage-gated sodium channels (VGSCs) are assembled from two classes of subunits, a pore-bearing α-subunit (NaV 1) and one or two accessory β-subunits (NaV βs). Neurons in mammals can express one or more of seven isoforms of NaV 1 and one or more of four isoforms of NaV β. The peptide μ-conotoxins, like the guanidinium alkaloids(More)