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Unformatted text preview: Jingzhaotoxin-I, a Novel Spider Neurotoxin Preferentially Inhibiting Cardiac Sodium Channel Inactivation* Received for publication, October 13, 2004, and in revised form, November 9, 2004 Published, JBC Papers in Press, November 17, 2004, DOI 10.1074/jbc.M411651200 Yucheng Xiao, Jianzhou Tang, Weijun Hu, Jinyun Xie, Chantal Maertens , Jan Tytgat, and Songping Liang From 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 inhibi- tor 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 (IC 50 31.6 n M ) is 30-fold higher than that for tetrodotoxin-sensitive subtypes in latter tissues. Not affecting outward delay- rectified potassium channels expressed in Xenopus lae- vis oocytes and tetrodotoxin-resistant sodium channels in mammal sensory neurons, JZTX-I hopefully repre- sents a potent ligand to discriminate cardiac sodium channels from neuronal tetrodotoxin-resistant iso- forms. 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 sub- class of spider sodium channel toxins. JZTX-I is an-like toxin first reported from spider venoms. The result pro- vides an important witness for a convergent functional evolution between spider and other animal venoms. Voltage-gated sodium channels (VGSCs) 1 are integral plasma membrane proteins composed of a pore-forming-sub- unit (260 kDa) associated with up to four auxiliary subunits (2123 kDa) (1, 2). VGSCs play a vital role in the initiation and propagation of exciting signals on most excitable tissues. Sim- ilar to the shaker potassium channel, the three-dimensional structure of sodium channel is a bell-shaped molecule (3, 4)....
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