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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 (21–23 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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- Spring '11
- Ecology, Disulfide bond, Sodium channel, sodium channel inactivation, JZTX-I