2007
DOI: 10.4161/chan.4847
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µO-Conotoxins Inhibit NaVChannels by Interfering with their Voltage Sensors in Domain-2

Abstract: ACKNOWLEDGEMENTSThis work was supported by the Deutsche Forschungsgemeinschaft (HE 2993/5-2 to Stefan H. Heinemann), FONACIT CNPq (PI 20040000385 to Adolfo Borges), and NIH (GM48677 to Baldomero M. Olivera). We thank Dr. J. Trimmer for providing the clone for rNa V 1.4 and the MzB SW seminar group for helpful discussions. ABSTRACTThe µO-conotoxins MrVIA and MrVIB are 31-residue peptides from Conus marmoreus, belonging to the O-superfamily of conotoxins with three disulfide bridges. They have attracted attent… Show more

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Cited by 67 publications
(79 citation statements)
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“…Recent estimates suggest that each species of cone snail produces hundreds to thousands of conotoxins, the majority of which remain pharmacologically uncharacterized [4,17]. Not surprisingly, many conotoxins affect action potential initiation and propagation, including the m-and mO-conotoxins that block the pore or alter Na V channel gating, [1,[18][19][20], the d-conotoxins that delay Na V inactivation by binding to site 6, and the i-conotoxins that enhance Na V channel opening [21][22][23]. While inhibition or enhanced activation of Na V can cause paralysis, cardiac arrhythmias or epilepsy in the case of central Na V , the precise role of conopeptides targeting Na V channels in prey capture and/or defence is unclear.…”
Section: Discussionmentioning
confidence: 99%
“…Recent estimates suggest that each species of cone snail produces hundreds to thousands of conotoxins, the majority of which remain pharmacologically uncharacterized [4,17]. Not surprisingly, many conotoxins affect action potential initiation and propagation, including the m-and mO-conotoxins that block the pore or alter Na V channel gating, [1,[18][19][20], the d-conotoxins that delay Na V inactivation by binding to site 6, and the i-conotoxins that enhance Na V channel opening [21][22][23]. While inhibition or enhanced activation of Na V can cause paralysis, cardiac arrhythmias or epilepsy in the case of central Na V , the precise role of conopeptides targeting Na V channels in prey capture and/or defence is unclear.…”
Section: Discussionmentioning
confidence: 99%
“…Accordingly, functional overlap with the ␤ scorpion toxin Ts1 was recently described, suggesting O conotoxins interact with the voltage sensor of Na v s (Leipold et al, 2007). Indeed, voltage-dependent relief of Na v 1.4 inhibition by MrVIB was attributed to the voltage sensor of domain II (Leipold et al, 2007), another site shared with ␤ scorpion toxins. Similar effects were also reported for Na v 1.8, where the K off of MrVIB was also accelerated by strong depolarizations (Wilson et al, 2011b).…”
Section: B O-conotoxin Inhibitors Of Voltage-gated Sodium Channelsmentioning
confidence: 99%
“…It is noteworthy that this site is also involved in ␤ scorpion toxin binding to site 4 , and both Na v 1.4 and Na v 1.8 share a homologous residue in this domain that is distinct from the other Na v subtypes and may contribute to the relative selectivity of MrVIA and MrVIB (Ekberg et al, 2006). Accordingly, functional overlap with the ␤ scorpion toxin Ts1 was recently described, suggesting O conotoxins interact with the voltage sensor of Na v s (Leipold et al, 2007). Indeed, voltage-dependent relief of Na v 1.4 inhibition by MrVIB was attributed to the voltage sensor of domain II (Leipold et al, 2007), another site shared with ␤ scorpion toxins.…”
Section: B O-conotoxin Inhibitors Of Voltage-gated Sodium Channelsmentioning
confidence: 99%
“…An estimate was made of the apparent charge transferred in the "gating" of kЈ off by assuming that K ϭ (Z g ϫ q e )/(k B ϫ T), where Z g is the gating charge, q e is the elementary charge (i.e., that of a proton), k B is Boltzmann's constant, and T is absolute temperature (c.f. Leipold et al, 2007; see also Hille, 2001). The factor q e /(k B ϫ T) has a value close to 1/25 mV Ϫ1 at room temperature, so Z g Ϸ25 mV ϫ K. It might be noted that the strong depolarizing pulses we used induced a potentiation of the I Na of oocytes expressing Na V 1.8.…”
Section: Methodsmentioning
confidence: 99%
“…Many of the more recently discovered ligands that target VGSCs are components of animal venoms (Al-Sabi et al, 2006;Billen et al, 2008). The peptide toxins from cone snail venoms are a particularly rich source (Terlau and Olivera, 2004), and at least four families of conopeptides target VGSCs, each via a different mechanism: -conotoxins, like the action of TTX and STX, block the channel's pore (Catterall et al, 2007); O-conotoxins are gating modifiers that block channel activation (Zorn et al, 2006;Heinemann and Leipold, 2007;Leipold et al, 2007); -conotoxins promote channel activation (Fiedler et al, 2008); and ␦-conotoxins inhibit fast inactivation (Leipold et al, 2005;West et al, 2005).…”
Section: Introductionmentioning
confidence: 99%