Multiple Actions of Phi-LITX-Lw1a on Ryanodine Receptors Reveal a Functional Link Between Scorpion DDH and ICK Toxins

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 May 15

PMID 23671114

Citations 18

Authors

Jennifer J Smith

Irina Vetter

Richard J Lewis

Steve Peigneur

Jan Tytgat

Alexander Lam

Esther M Gallant

Nicole A Beard

Paul F Alewood

Angela F Dulhunty

Affiliations

Soon will be listed here.

Abstract

We recently reported the isolation of a scorpion toxin named U1-liotoxin-Lw1a (U1-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 U1-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, U1-LITX-Lw1a, now described as ϕ-liotoxin-Lw1a (ϕ-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 ϕ-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. ϕ-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.

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References

Esteve E, Mabrouk K, Dupuis A, Smida-Rezgui S, Altafaj X, Grunwald D . Transduction of the scorpion toxin maurocalcine into cells. Evidence that the toxin crosses the plasma membrane. J Biol Chem. 2005; 280(13):12833-9. PMC: 2713311. DOI: 10.1074/jbc.M412521200. View

Chen L, Esteve E, Sabatier J, Ronjat M, De Waard M, Allen P . Maurocalcine and peptide A stabilize distinct subconductance states of ryanodine receptor type 1, revealing a proportional gating mechanism. J Biol Chem. 2003; 278(18):16095-106. DOI: 10.1074/jbc.M209501200. View

Ullrich N, Valdivia H, Niggli E . PKA phosphorylation of cardiac ryanodine receptor modulates SR luminal Ca2+ sensitivity. J Mol Cell Cardiol. 2012; 53(1):33-42. PMC: 3674825. DOI: 10.1016/j.yjmcc.2012.03.015. View

Martin C, Chapman K, Seckl J, Ashley R . Partial cloning and differential expression of ryanodine receptor/calcium-release channel genes in human tissues including the hippocampus and cerebellum. Neuroscience. 1998; 85(1):205-16. DOI: 10.1016/s0306-4522(97)00612-x. View

Yotsu-Yamashita M, Kim Y, Dudley Jr S, Choudhary G, Pfahnl A, Oshima Y . The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: a potent sodium-channel blocker. Proc Natl Acad Sci U S A. 2004; 101(13):4346-51. PMC: 384749. DOI: 10.1073/pnas.0400368101. View

Meissner G . Ryanodine as a functional probe of the skeletal muscle sarcoplasmic reticulum Ca2+ release channel. Mol Cell Biochem. 1992; 114(1-2):119-23. DOI: 10.1007/BF00240306. View

Lokuta A, Arevalo C, Valdivia H . Peptide probe of ryanodine receptor function. Imperatoxin A, a peptide from the venom of the scorpion Pandinus imperator, selectively activates skeletal-type ryanodine receptor isoforms. J Biol Chem. 1995; 270(48):28696-704. DOI: 10.1074/jbc.270.48.28696. View

Priori S, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R . Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001; 103(2):196-200. DOI: 10.1161/01.cir.103.2.196. View

Tripathy A, Resch W, Xu L, Valdivia H, Meissner G . Imperatoxin A induces subconductance states in Ca2+ release channels (ryanodine receptors) of cardiac and skeletal muscle. J Gen Physiol. 1998; 111(5):679-90. PMC: 2217137. DOI: 10.1085/jgp.111.5.679. View

10.

Gonzalez D, Treuer A, Castellanos J, Dulce R, Hare J . Impaired S-nitrosylation of the ryanodine receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure. J Biol Chem. 2010; 285(37):28938-45. PMC: 2937920. DOI: 10.1074/jbc.M110.154948. View

11.

Ahern G, Junankar P, Dulhunty A . Single channel activity of the ryanodine receptor calcium release channel is modulated by FK-506. FEBS Lett. 1994; 352(3):369-74. DOI: 10.1016/0014-5793(94)01001-3. View

12.

Dulhunty A, Casarotto M, Beard N . The ryanodine receptor: a pivotal Ca2+ regulatory protein and potential therapeutic drug target. Curr Drug Targets. 2011; 12(5):709-23. DOI: 10.2174/138945011795378595. View

13.

Takano K, Liu D, Tarpey P, Gallant E, Lam A, Witham S . An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity. Hum Mol Genet. 2012; 21(20):4497-507. PMC: 3459470. DOI: 10.1093/hmg/dds292. View

14.

Rush A, Cummins T, Waxman S . Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol. 2006; 579(Pt 1):1-14. PMC: 2075388. DOI: 10.1113/jphysiol.2006.121483. View

15.

Mabrouk K, Ram N, Boisseau S, Strappazzon F, Rehaim A, Sadoul R . Critical amino acid residues of maurocalcine involved in pharmacology, lipid interaction and cell penetration. Biochim Biophys Acta. 2007; 1768(10):2528-40. DOI: 10.1016/j.bbamem.2007.06.030. View

16.

Mosbah A, Kharrat R, Fajloun Z, Renisio J, Blanc E, Sabatier J . A new fold in the scorpion toxin family, associated with an activity on a ryanodine-sensitive calcium channel. Proteins. 2000; 40(3):436-42. DOI: 10.1002/1097-0134(20000815)40:3<436::aid-prot90>3.0.co;2-9. View

17.

Fry B, Roelants K, Champagne D, Scheib H, Tyndall J, King G . The toxicogenomic multiverse: convergent recruitment of proteins into animal venoms. Annu Rev Genomics Hum Genet. 2009; 10:483-511. DOI: 10.1146/annurev.genom.9.081307.164356. View

18.

Koch G . The endoplasmic reticulum and calcium storage. Bioessays. 1990; 12(11):527-31. DOI: 10.1002/bies.950121105. View

19.

Sun H, Greathouse D, Andersen O, Koeppe 2nd R . The preference of tryptophan for membrane interfaces: insights from N-methylation of tryptophans in gramicidin channels. J Biol Chem. 2008; 283(32):22233-43. PMC: 2494914. DOI: 10.1074/jbc.M802074200. View

20.

Rodriguez de la Vega R, Possani L . Overview of scorpion toxins specific for Na+ channels and related peptides: biodiversity, structure-function relationships and evolution. Toxicon. 2005; 46(8):831-44. DOI: 10.1016/j.toxicon.2005.09.006. View