Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins

Jennifer J. Smith, Irina Vetter, Richard J. Lewis, Steve Peigneur, Jan Tytgat, Alexander Lam, Esther M. Gallant, Nicole BEARD, Paul F. Alewood, Angela F. Dulhunty

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

We recently reported the isolation of a scorpion toxin named U-1-liotoxin-Lw1a (U-1-LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U-1-LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U-1-LITX-Lw1a, now described as phi-liotoxin-Lw1a (phi-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of phi-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. phi-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia
Original languageEnglish
Pages (from-to)8906-8911
Number of pages6
JournalNational Academy of Sciences. Proceedings
Volume110
Issue number22
DOIs
Publication statusPublished - 2013

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Scorpions
Ryanodine Receptor Calcium Release Channel
Cystine
Disulfides
Cystine Knot Motifs
Malignant Hyperthermia
Ventricular Tachycardia
Binding Sites
Pharmacology

Cite this

Smith, Jennifer J. ; Vetter, Irina ; Lewis, Richard J. ; Peigneur, Steve ; Tytgat, Jan ; Lam, Alexander ; Gallant, Esther M. ; BEARD, Nicole ; Alewood, Paul F. ; Dulhunty, Angela F. / Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins. In: National Academy of Sciences. Proceedings. 2013 ; Vol. 110, No. 22. pp. 8906-8911.
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abstract = "We recently reported the isolation of a scorpion toxin named U-1-liotoxin-Lw1a (U-1-LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U-1-LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U-1-LITX-Lw1a, now described as phi-liotoxin-Lw1a (phi-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of phi-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. phi-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia",
keywords = "Skeletal muscle, calcium channels, toxins",
author = "Smith, {Jennifer J.} and Irina Vetter and Lewis, {Richard J.} and Steve Peigneur and Jan Tytgat and Alexander Lam and Gallant, {Esther M.} and Nicole BEARD and Alewood, {Paul F.} and Dulhunty, {Angela F.}",
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Smith, JJ, Vetter, I, Lewis, RJ, Peigneur, S, Tytgat, J, Lam, A, Gallant, EM, BEARD, N, Alewood, PF & Dulhunty, AF 2013, 'Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins', National Academy of Sciences. Proceedings, vol. 110, no. 22, pp. 8906-8911. https://doi.org/10.1073/pnas.1214062110

Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins. / Smith, Jennifer J.; Vetter, Irina; Lewis, Richard J.; Peigneur, Steve; Tytgat, Jan; Lam, Alexander; Gallant, Esther M.; BEARD, Nicole; Alewood, Paul F.; Dulhunty, Angela F.

In: National Academy of Sciences. Proceedings, Vol. 110, No. 22, 2013, p. 8906-8911.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins

AU - Smith, Jennifer J.

AU - Vetter, Irina

AU - Lewis, Richard J.

AU - Peigneur, Steve

AU - Tytgat, Jan

AU - Lam, Alexander

AU - Gallant, Esther M.

AU - BEARD, Nicole

AU - Alewood, Paul F.

AU - Dulhunty, Angela F.

PY - 2013

Y1 - 2013

N2 - We recently reported the isolation of a scorpion toxin named U-1-liotoxin-Lw1a (U-1-LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U-1-LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U-1-LITX-Lw1a, now described as phi-liotoxin-Lw1a (phi-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of phi-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. phi-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia

AB - We recently reported the isolation of a scorpion toxin named U-1-liotoxin-Lw1a (U-1-LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U-1-LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U-1-LITX-Lw1a, now described as phi-liotoxin-Lw1a (phi-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of phi-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. phi-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia

KW - Skeletal muscle

KW - calcium channels

KW - toxins

U2 - 10.1073/pnas.1214062110

DO - 10.1073/pnas.1214062110

M3 - Article

VL - 110

SP - 8906

EP - 8911

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

SN - 0027-8424

IS - 22

ER -