ProTx-I and ProTx-II: Gating modifiers of voltage-gated sodium channels

Priest, Birgit T.; Blumenthal, Kenneth M.; Smith, Jaime J.; Warren, Vivien A.; Smith, McHardy M.

doi:10.1016/j.toxicon.2006.09.014

Cited by 66 publications

(58 citation statements)

References 36 publications

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“…Spider venom toxins such as the ı-atracotoxins, Magi5, CcoTx1, CcoTx2, CcoTx3, and ProTx-II [10,22,25,27,29,35] shift the threshold of VGSC activation to more negative or positive potentials. Therefore, we investigated the effect of subsaturating toxin concentrations on the voltage dependence of current activation.…”

Section: Voltage-dependent Hntx-iv Inhibition Of Hnav17 Expressed Onmentioning

confidence: 99%

Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels

et al. 2015

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Section: Voltage-dependent Hntx-iv Inhibition Of Hnav17 Expressed Onmentioning

confidence: 99%

Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels

et al. 2015

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“…In regard to Nav1.7, promising results have been obtained with the cystine-knot toxin ProTx-II from tarantula (Thrixopelma pruriens). ProTx-II shifts the activation of VGSCs toward more depolarized potentials and appears to have a preference for the Nav1.7 subtype [40,86,95,109]. Recordings of compound action potentials from peripheral nerves revealed that ProTx-II can potently block nociceptive C-fibers without affecting nonnociceptive A-fibers [104].…”

Section: Mutation-selective Therapy For Iem and Pepd?mentioning

confidence: 99%

Sodium channelopathies and pain

Lampert

O’Reilly

Reeh

et al. 2010

Pflugers Arch - Eur J Physiol

112

105

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Chronic pain often represents a severe, debilitating condition. Up to 10% of the worldwide population are affected, and many patients are poorly responsive to current treatment strategies. Nociceptors detect noxious conditions to produce the sensation of pain, and this signal is conveyed to the CNS by means of action potentials. The fast upstroke of action potentials is mediated by voltage-gated sodium channels, of which nine pore-forming alpha-subunits (Nav1.1-1.9) have been identified. Heterogeneous functional properties and distinct expression patterns denote specialized functions of each subunit. The Nav1.7 and Nav1.8 subunits have emerged as key molecules involved in peripheral pain processing and in the development of an increased pain sensitivity associated with inflammation and tissue injury. Several mutations in the SCN9A gene encoding for Nav1.7 have been identified as important cellular substrates for different heritable pain syndromes. This review aims to cover recent progress on our understanding of how biophysical properties of mutant Nav1.7 translate into an aberrant electrogenesis of nociceptors. We also recapitulate the role of Nav1.8 for peripheral pain processing and of additional sodium channelopathies which have been linked to disorders with pain as a significant component.

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“…Voltage-sensor trapping by both ␣-and ␤-scorpion toxins inhibits gating currents generated by the transmembrane movement of the S4 segments, providing a mechanistic signature for voltage-sensor trapping (Nonner, 1979;Meves et al, 1982). The polypeptide toxins from the tarantula Thrixopelma pruriens (Protoxins) are members of the inhibitory cysteineknot family of protein toxins, consisting of 30 to 35 amino acid residues with three disulfide bridges (Norton and Pallaghy, 1998;Middleton et al, 2002;Priest et al, 2007). This family includes toxins that inhibit activation of sodium channels, such as ProTx-II, and potassium channels, such as hanatoxin, by interfering with the normal function of the voltage sensors (Swartz and MacKinnon, 1997;Middleton et al, 2002).…”

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confidence: 99%

Inhibition of Sodium Channel Gating by Trapping the Domain II Voltage Sensor with Protoxin II

Sokolov¹,

Kraus²,

Scheuer³

et al. 2007

Mol Pharmacol

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ProTx-II, an inhibitory cysteine knot toxin from the tarantula Thrixopelma pruriens, inhibits voltage-gated sodium channels. Using the cut-open oocyte preparation for electrophysiological recording, we show here that ProTx-II impedes movement of the gating charges of the sodium channel voltage sensors and reduces maximum activation of sodium conductance. At a concentration of 1 M, the toxin inhibits 65.3 Ϯ 4.1% of the sodium conductance and 24.6 Ϯ 6.8% of the gating current of brain Na v 1.2a channels, with a specific effect on rapidly moving gating charge. Strong positive prepulses can reverse the inhibitory effect of ProTx-II, indicating voltage-dependent dissociation of the toxin. Voltage-dependent reversal of the ProTx-II effect is more rapid for cardiac Na v 1.5 channels, suggesting subtype-specific action of this toxin. Voltage-dependent binding and block of gating current are hallmarks of gating modifier toxins, which act by binding to the extracellular end of the S4 voltage sensors of ion channels. The mutation L833C in the S3-S4 linker in domain II reduces affinity for ProTx-II, and mutation of the outermost two gating-charge-carrying arginine residues in the IIS4 voltage sensor to glutamine abolishes voltage-dependent reversal of toxin action and toxin block of gating current. Our results support a voltage-sensor-trapping model for ProTx-II action in which the bound toxin impedes the normal outward gating movement of the IIS4 transmembrane segment, traps the domain II voltage sensor module in its resting state, and thereby inhibits channel activation.

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ProTx-I and ProTx-II: Gating modifiers of voltage-gated sodium channels

Cited by 66 publications

References 36 publications

Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels

Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels

Sodium channelopathies and pain

Inhibition of Sodium Channel Gating by Trapping the Domain II Voltage Sensor with Protoxin II

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