Expanding the scorpion toxin α‐KTX 15 family with AmmTX3 from <i>Androctonus mauretanicus</i>

Vacher, Hélène; Alami, Mériem; Crest, Marcel; Possani, Lourival D.; Bougis, Pierre E.; Martin‐Eauclaire, Marie‐France

doi:10.1046/j.1432-1033.2002.03294.x

Cited by 53 publications

(40 citation statements)

References 21 publications

(30 reference statements)

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“…Remarkably, SNX-482 has higher potency against cloned Kv4.3 than any of the other inhibitors yet described, including phrixotoxins (Diochot et al, 1999), AmmTX3 (Vacher et al, 2002;Maffie et al, 2013), and heteropodatoxin (Sanguinetti et al, 1997). Like SNX-482, heteropodatoxin is an ICK toxin that acts by shifting activation to more depolarized potentials and by slowing inactivation (Zarayskiy et al, 2005;DeSimone et al, 2009).…”

Section: Discussionmentioning

confidence: 96%

Inhibition of A-Type Potassium Current by the Peptide Toxin SNX-482

Kimm

Bean

2014

Journal of Neuroscience

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SNX-482, a peptide toxin isolated from tarantula venom, has become widely used as an inhibitor of Cav2.3 voltage-gated calcium channels. Unexpectedly, we found that SNX-482 dramatically reduced the A-type potassium current in acutely dissociated dopamine neurons from mouse substantia nigra pars compacta. The inhibition persisted when calcium was replaced by cobalt, showing that it was not secondary to a reduction of calcium influx. Currents from cloned Kv4.3 channels expressed in HEK-293 cells were inhibited by SNX-482 with an IC 50 of Ͻ3 nM, revealing substantially greater potency than for SNX-482 inhibition of Cav2.3 channels (IC 50 20 -60 nM). At sub-saturating concentrations, SNX-482 produced a depolarizing shift in the voltage dependence of activation of Kv4.3 channels and slowed activation kinetics. Similar effects were seen on gating of cloned Kv4.2 channels, but the inhibition was less pronounced and required higher toxin concentrations. These results reveal SNX-482 as the most potent inhibitor of Kv4.3 channels yet identified. Because of the effects on both Kv4.3 and Kv4.2 channels, caution is needed when interpreting the effects of SNX-482 on cells and circuits where these channels are present.

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Section: Discussionmentioning

confidence: 96%

Inhibition of A-Type Potassium Current by the Peptide Toxin SNX-482

Kimm

Bean

2014

Journal of Neuroscience

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“…Binding and displacement experiments using rat brain synaptosomes showed that AmmTX3 and Aa1 competed effectively with 125 I-labeled sBmTX3 binding. They fully inhibited the 125 I-labeled sBmTX3 binding (Ki values of 19.5 pM and 44.2 pM, respectively), demonstrating unambiguously that the three molecules shared the same target in rat brain (Vacher et al 2002). BmTX3 inhibits the A-type current of Kv4.1-3 transfected into COS-7 cells (Vacher et al 2006).…”

mentioning

confidence: 79%

Kv4 potassium channels modulate hippocampal EPSP-spike potentiation and spatial memory in rats

Truchet¹,

Manrique²,

Sréng³

et al. 2012

Learn. Mem.

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Kv4 channels regulate the backpropagation of action potentials (b-AP) and have been implicated in the modulation of longterm potentiation (LTP). Here we showed that blockade of Kv4 channels by the scorpion toxin AmmTX3 impaired reference memory in a radial maze task. In vivo, AmmTX3 intracerebroventricular (i.c.v.) infusion increased and stabilized the EPSP-spike (E-S) component of LTP in the dentate gyrus (DG), with no effect on basal transmission or short-term plasticity. This increase in E-S potentiation duration could result from the combination of an increase in excitability of DG granular cells with a reduction of GABAergic inhibition, leading to a strong reduction of input specificity. Radioactive in situ hybridization (ISH) was used to evaluate the amounts of Kv4.2 and Kv4.3 mRNA in brain structures at different stages of a spatial learning task in naive, pseudoconditioned, and conditioned rats. Significant differences in Kv4.2 and Kv4.3 mRNA levels were observed between conditioned and pseudoconditioned rats. Kv4.2 and Kv4.3 mRNA levels were transiently up-regulated in the striatum, nucleus accumbens, retrosplenial, and cingulate cortices during early stages of learning, suggesting an involvement in the switch from egocentric to allocentric strategies. Spatial learning performance was positively correlated with the levels of Kv4.2 and Kv4.3 mRNAs in several of these brain structures. Altogether our findings suggest that Kv4 channels could increase the signal-to-noise ratio during information acquisition, thereby allowing a better encoding of the memory trace.

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“…In some experiments, we followed application of paxilline and guangxitoxin-1E with a solution designed to block all potassium currents. This solution contained the following (in mM): 155 TEA, 10 HEPES, 13 glucose, 1.5 CaCl 2 , 1 MgCl 2 , 10 4-aminopyridine, with 1 M AmmTx3 (Vacher et al, 2002), and 1 M TTX.…”

Section: Electrophysiologic Recordings With Dissociated Neuronsmentioning

confidence: 99%

“…As noted previously, the total potassium current flowing during the action potential repolarization is larger than the net outward current, because inward calcium current also flows during the action potential repolarization (Puopolo et al, 2007). In the experiment of Figure 7A, we followed the application of paxilline and GxTX-1E by applying a solution designed to inhibit all potassium currents, in which sodium was replaced by 155 mM TEA, together with 10 mM 4-aminopyridine and the Kv4-channel blocker AmmTx3 (Vacher et al, 2002;Amendola et al, 2012). This solution blocked additional outward current compared with paxilline and GxTX-1E together, revealing an inward current, likely carried by calcium channels, during the falling phase of the action potential.…”

Section: Action Potential-evoked Bk and Kv2 Currents In Dissociated Nmentioning

confidence: 99%

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

2015

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Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency-current ( f-I) relationship, whereas BK channel inhibition had little effect on the f-I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f-I relationship. The crossregulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell.

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Expanding the scorpion toxin α‐KTX 15 family with AmmTX3 from Androctonus mauretanicus

Cited by 53 publications

References 21 publications

Inhibition of A-Type Potassium Current by the Peptide Toxin SNX-482

Inhibition of A-Type Potassium Current by the Peptide Toxin SNX-482

Kv4 potassium channels modulate hippocampal EPSP-spike potentiation and spatial memory in rats

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

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