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J. Biol. Chem., Vol. 280, Issue 13, 12069-12076, April 1, 2005

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Jingzhaotoxin-I, a Novel Spider Neurotoxin Preferentially Inhibiting Cardiac Sodium Channel Inactivation^*

Yucheng Xiao, Jianzhou Tang, Weijun Hu, Jinyun Xie, Chantal Maertens||, Jan Tytgat, and Songping Liang¶

From the College of Life Sciences, Hunan Normal University, Changsha 410081, China and Laboratory of Toxicology, University of Leuven, E. Van Evenstraat 4, 3000 Leuven, Belgium

Jingzhaotoxin-I (JZTX-I), a 33-residue polypeptide, is derived from the Chinese tarantula Chilobrachys jing-zhao venom based on its ability to evidently increase the strength and the rate of vertebrate heartbeats. The toxin has three disulfide bonds with the linkage of I-IV, II-V, and III-VI that is a typical pattern found in inhibitor cystine knot molecules. Its cDNA determined by rapid amplification of 3'- and 5'-cDNA ends encoded a 62-residue precursor with a small proregion of eight residues. Whole-cell configuration indicated that JZTX-I was a novel neurotoxin preferentially inhibiting cardiac sodium channel inactivation by binding to receptor site 3. Although JZTX-I also exhibits the interaction with channel isoforms expressing in mammalian and insect sensory neurons, its affinity for tetrodotoxin-resistant subtype in mammalian cardiac myocytes (IC₅₀ = 31.6 nM) is 30-fold higher than that for tetrodotoxin-sensitive subtypes in latter tissues. Not affecting outward delay-rectified potassium channels expressed in Xenopus laevis oocytes and tetrodotoxin-resistant sodium channels in mammal sensory neurons, JZTX-I hopefully represents a potent ligand to discriminate cardiac sodium channels from neuronal tetrodotoxin-resistant isoforms. Furthermore, different from any reported spider toxins, the toxin neither modifies the current-voltage relationships nor shifts the steady-state inactivation of sodium channels. Therefore, JZTX-I defines a new subclass of spider sodium channel toxins. JZTX-I is an -like toxin first reported from spider venoms. The result provides an important witness for a convergent functional evolution between spider and other animal venoms.

Received for publication, October 13, 2004 , and in revised form, November 9, 2004.

^* This work was supported by National Natural Science Foundation of China under contract number 30430170 and by Grant G.0081.02 (to F. W. O.-Vlaanderen). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| A postdoctoral research fellow (postdoctoral onderzoeker of the Fund for Scientific Research-Flanders (F. W. O.-Vlaanderen).

^¶ To whom correspondence should be addressed: College of Life Sciences, Hunan Normal University, Changsha 410081, China. Tel.: 86-731-8872556; Fax: 86-731-8861304; E-mail: liangsp{at}hunnu.edu.cn.

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