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Scorpion Toxins Targeted Against the Sarcoplasmic Reticulum Ca2+-Release Channel of Skeletal and Cardiac Muscle

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Scorpion Toxins Targeted Against the Sarcoplasmic Reticulum Ca2+-Release Channel of Skeletal and Cardiac Muscle Proc. Nati. Acad. Sci. USA Vol. 89, pp. 12185-12189, December 1992 Physiology Scorpion toxins targeted against the sarcoplasmic reticulum Ca2+-release channel of skeletal and cardiac muscle (ryanodine receptors/Pandinus imperator venom/planar bilayer/ventricular myocytes/Ca2+ indicator) HECTOR H. VALDIVIA*t, MARK S. KIRBYf, W. JONATHAN LEDERER*, AND ROBERTO CORONADO*t *Department of Physiology, University of Wisconsin School of Medicine, Madison, WI 53706; and tDepartment of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201 Communicated by Michael V. L. Bennett, September 21, 1992 ABSTRACT We report the purification of two peptides, peratoxin inhibitor (IpTxi)] or activated [imperatoxin activa- called "imperatoxin inhibitor" and "imperatoxin activator," tor (IpTxa)] ryanodine receptors of skeletal and cardiac from the venom of the scorpion Pandinus imperator targeted muscle. Part of these results have been communicated in an against ryanodine receptor Ca2+-release channels. Impera- abstract form (8). toxin inhibitor has a Mr of 10,500, inhibits [3Hjryanodine binding to skeletal and cardiac sarcoplasmic reticulum with an EDso of 10 nM, and blocks openings of skeletal and cardiac EXPERIMENTAL PROCEDURES Ca2+-release channels incorporated into planar bilayers. In Purification of Scorpion Toxins. Lyophilized P. imperator whole-cell recordings of cardiac myocytes, imperatoxin inhib- venom was obtained from Latoxan (Rosans, France). Venom itor decreased twitch amplitude and intracellular Ca2+ tran- (50 mg per batch) was extracted in 2-3 ml of deionized water sients, suggesting a selective blockade of Ca2+ release from the and chromatographed on a column (1. 5 x 125 cm) of Sepha- sarcoplasmic reticulum. Imperatoxin activator has a Mr of dex G-50 fine. Fractions were eluted with 20 mM NaOAc (pH -8700, stimulates [3H]ryanodine bind in skeletal but not 4.7) at a flow rate of 10 ml/hr. Fraction II containing IpTxi cardiac sarcoplasmic reticulum with an ED50 of -6 nM, and and fraction III containing IpTxa described in Fig. 1B were activates skeletal but not cardiac Ca2+-release channels. These applied separately to a column (1 x 25 cm) of carboxymethyl ligands may serve to selectively "turn on" or "turn off" (CM)-cellulose 32 (Pharmacia) equilibrated with 20 mM ryanodine receptors in fragmented systems and whole cells. NaOAc (pH 4.7). Peptides were eluted at a flow rate of 12 ml/hr with a linear gradient of 250 ml of 20 mM NaOAc (pH Activation of muscle, neurons, and secretory cells by volt- 4.7) and 250 ml of the same buffer containing 0.5 M NaCl. A age, neurotransmitters, or hormones can evoke a release of peptide from fraction II containing >90% of the inhibitory Ca2+ from intracellular Ca2+ stores (1). Two types of Ca2+ activity (IpTxi) and a peptide from fraction III containing channels, namely ryanodine receptors and inositol 1,4,5- >90% ofthe stimulatory activity (IpTxa) were eluted as single trisphosphate (InsP3) receptors, have been shown to control symmetric peaks when the NaCl concentration at the top of the intracellular Ca2+ permeability of many cells. In striated the CM-cellulose 32 column reached 65 and 340 mM, respec- muscle, these channels transduce membrane voltage, sar- tively. IpTxi and IpTx. were dialyzed against deionized water colemmal Ca2+ entry, and other external stimuli into an in Spectrapor 3M dialysis membrane (Spectrum Medical increase in the Ca2+ permeability of the sarcoplasmic retic- Industries), concentrated by vacuum centrifugation, and ulum (SR) (2). Elucidation of the mechanism of Ca2+ release injected into a C18 reverse-phase HPLC column (,uBondapac, from intracellular stores depends critically on the specificity Waters Associates). IpTxi and IpTxa were eluted with a linear of pharmacological agents to selectively alter a single intra- gradient of5-80o acetonitrile in 0.1% trifluoroacetic acid run cellular Ca2+ channel type. The alkaloid ryanodine is pres- at 1 ml/min for 60 min. ently the only ligand available to dissect the contribution of Binding Assays. [3H]Ryanodine [60 mCi/mmol (1 Ci = 37 ryanodine receptors to intracellular Ca2+ release in situ. GBq); DuPont/New England Nuclear] binding was carried However, the usefulness of this compound is limited by the out as described (9) for 90 min at 36TC in 0.2 M KCl/1 mM fact that it has an extremely slow association and dissociation Na2EGTA/0.995 mM CaCl2 (10 AuM free Ca2+; ref. 9)/10 mM kinetics that makes the onset of the pharmacological effect sodium Pipes, pH 7.2. Binding of [3H]saxitoxin, [3H]ouabain, slow and essentially irreversible (3). To accelerate the onset, and [3H]PN200-110 was carried out in rabbit skeletal muscle micromolar instead of nanomolar levels of ryanodine are transverse tubular membranes as described (10). Binding of used, but at micromolar concentrations the alkaloid inhibits [3H]quinuclinidyl benzylate was carried out in bovine cardiac other Ca2+ channels (4). Furthermore, certain concentrations sarcolemma as described (11). Binding of [3H]InsP3 was ofryanodine may open the Ca2+-release channel while others carried out in rat brain microsomes as described (12). may block it (5), leading to ambiguous results (6). Alternative Ca2+ Transients and Twitch Recordings. Adult rat ventric- ligands that act fast, reversibly, and in a simple manner ular myocytes were isolated by using a standard collagenase should be more helpful in establishing the contribution of dispersion technique (13). Myocytes were constantly super- ryanodine receptors to intracellular Ca2+ signals. fused at 350C in a chamber mounted on the stage of an Scorpion venoms have traditionally represented an invalu- inverted microscope. Intracellular dialysis was achieved by able source ofpeptide toxins specific for a single channel type using standard patch-clamp electrodes (2 to 5 Mohms) with (7). In the present report, we screened venom from several the whole-cell configuration, in which the pipette ruptured genera of scorpions with the hope offinding peptides specific the cell for insertion of the electrode. Myocyte length was for ryanodine receptors. We purified two peptides from the measured with a video-based edge detector. Indo-1 fluores- venom of Pandinus imperator that selectively blocked [im- Abbreviations: SR, sarcoplasmic reticulum; IpTxa and IpTxi, impera- The publication costs of this article were defrayed in part by page charge toxin activator and inhibitor, respectively; InsP3, inositol 1,4,5- payment. This article must therefore be hereby marked "advertisement" trisphosphate. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 12185 Downloaded by guest on September 30, 2021 12186 Physiology: Valdivia et al. Proc. Nati. Acad. Sci. USA 89 (1992) BSA Cyt C NaC y Y - 30C B 0.8 + c .0 C - 20C0: -0 0.6- PI 1F5 a) aC .C I cc 1 -o < 0.44- IV _0 0 To cx 0.2 t -0 o I co, t 50o m 0.0j I.I-r-- 0 0.1 1 10 100 1000 40 BC 20 I 6C 20C P. imperator venom, tg/ml Elution volume. ml FIG. 1. (A) Effect ofPandinus venom on the binding of7 nM [3H]ryanodine to cardiac (e) and skeletal (o) SR vesicles, which was measured in the absence (control, 100%) and in the presence of the indicated concentrations of Pandinus venom. Binding in control was 1.8 and 0.42 pmol/mg ofprotein for skeletal and cardiac SR, respectively. For other species results (numbers after the species represent skeletal SR binding activity in pmol/mg ± SD in the presence of800 j.g/ml of venom; numbers in parentheses are the percent binding ofcontrol) were Androctonus mauritanicus, 1.83 ± 0.32 (102%); Androctonus australis, 1.26 0.40(70%); Buthus arenicola, 1.93 0.44 (107%); Buthus occitanus mardochei, 2.16 ± 0.46 (120%o); Buthus occitanus tunetanus, 2.10 ± 0.28 (118%o); Buthotus hottentota, 6.75 ± 1.22 (375%); Buthotusjudaicus, 6.26 ± 1.11 (348%); Leiurus quinquestriatus, 2.46 ± 0.60 (137%); and Leiurus g. hebraeus, 2.09 ± 0.39 (116%). (B) Chromatographic profile of Pandinus venom and effect of venom fractions on PH]ryanodine binding. Pandinus venom was loaded on a Sephadex G-50 column and eluted with 20 mM NaOAc (pH 4.7) as described in text. Fractions (5 ml) were collected and pooled as indicated by the shaded bars. Fractions I through VI (5 ,.g/ml) were assayed for effects on [3H]ryanodine binding to skeletal SR. Elution ofmolecular weight markers is indicated by the arrowheads. BSA, bovine serum albumin; Cyt C, cytochrome c. cence was measured and calibrated at 350C as described (14). Others. Skeletal and cardiac SR were prepared from rabbit The control electrode back-filling solution contained 122 mM back and leg white muscle or bovine myocardium in the KCl, 2.25 mM KH2PO4, 6 mM MgC2, 5 mM K2ATP, 9 mM presence of protease inhibitors as described for skeletal SR Hepes, 3.6 mM sodium creatine phosphate, and 0.05 mM (15). Planar bilayer composition and CsCl solutions used in cis K5Indo-1, with pH adjusted to 7.15 at 350C with KOH. IpTxi and trans chambers have been described (16). Samples for (1 AM) was always added to the back-filling solution. The SDS/PAGE (sodium dodecyl sulfate/polyacrylamide gel elec- superfusing solution contained 118 mM NaCl, 4.75 mM KCI, trophoresis) were incubated for 15 min at 800C in 2% SDS/2% 0.9 mM KH2PO4, 1.2 mM MgSO4, 5 mM Hepes, 5 mM (vol/vol) 2-mercaptoethanol/1O% (vol/vol) glycerol/10 mM sodium Hepes, and 10 mM glucose, with pH adjusted to 7.4 Tris (pH 6.8) and run on a 6-15% linear polyacrylamide gel at 350C with NaOH. After establishing the whole-cell con- gradient. Gels were stained with 0.05% Coomassie blue R in figuration, there was a small depolarization from -72 + 2.5 10o acetic acid.
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