© 1997 American Heart Association, Inc.
Articles |
Effects of Tityus serrulatus Scorpion Toxin 
on Voltage-Gated Na+ Channels
Laval Hospital (P.M., M.C.), Research Center, Quebec, Canada, and the Department of Biochemistry and Biophysics (L.-Q.C., R.G.K.), University of Pennsylvania School of Medicine, Philadelphia.
Correspondence to Dr M. Chahine, Laval Hospital, Research Center, 2725, Chemin Ste-Foy, Quebec, Canada, G1V 4G5. E-mail mohamed.chahine@phc.ulaval.ca
The effects of Brazilian scorpion Tityus serrulatus toxin (TiTx) were studied on voltage-gated Na+ channels from human heart (hH1) and rat skeletal muscle (rSkM1). The Na+ channels were expressed in Xenopus laevis oocytes, and Na+ currents were recorded using two-microelectrode voltage-clamp techniques. In control experiments, the threshold of activation of hH1 is more negative than that of rSkM1 by 
20 mV. The toxin induces a shift of the voltage dependence of activation toward more negative potential values and reduces the amplitude of the current when administered to rSkM1. In contrast, TiTx has little discernible effect on the current-voltage curve for hH1 at 100 nmol/L. Chimeric channels formed from these two isoforms were constructed to localize the binding site of TiTx on rSkM1. TiTx shifts the activation of a chimera (SSHH) in which domains 1 (D1) and 2 (D2) derive from rSkM1 and domains 3 (D3) and 4 (D4) derive from hH1. This finding suggests that the toxin acts on the activation of rSkM1 by binding either to D1 and/or D2. TiTx shifted the activation of another chimera with D2-D3-D4 from rSkM1 (HSSS) toward more hyperpolarizing potentials and had no effect on the activation of other chimeras with only D1-D3-D4 from rSkM1 (SHSS) or only D3 from rSkM1 (HHSH). Finally, a chimera in which D2 is from rSkM1 and all others domains are from hH1 (HSHH) provides further compelling support for our hypothesis. TiTx shifts the activation of this chimera toward more negative potential values. Thus, TiTx action on chimeras segregates with the source of D2: when D2 is from rSkM1, the toxin affects activation. We infer that D2 plays an important role in the activation process of voltage-gated Na+ channels.
Key Words: sodium channel • Tityus serrulatus toxin • voltage clamp • rat skeletal muscle • human cardiac muscle
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