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The Journal of Neuroscience, June 15, 1998, 18(12):4473-4481
µ-Conotoxin PIIIA, a New Peptide for Discriminating among Tetrodotoxin-Sensitive Na Channel Subtypes
Ki-Joon Shon1, Baldomero M. Olivera2, Maren Watkins3, Richard B. Jacobsen2, William R. Gray2, Christina Z. Floresca2, 4, Lourdes J. Cruz2, 4, David R. Hillyard3, Anette Brink5, Heinrich Terlau5, and Doju Yoshikami2 1 Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, Departments of 2 Biology and 3 Pathology, University of Utah, Salt Lake City, Utah 84112, 4 Marine Science Institute, University of the Philippines, Quezon City, 1101 Philippines, and 5 Molekulare Biologie Neuronaler Signale, Max-Planck-Institut für experimentelle Medizin, D-37075 Göttingen, Germany
where Z = pyroglutamate and O = 4-trans-hydroxyproline.
We demonstrate that Arginine-14 (Arg14) is a key residue; substitution by alanine significantly decreases affinity and results in a toxin unable to block channel conductance completely. Thus, like all toxins that block at Site I, µ-PIIIA has a critical guanidinium group.
This peptide is of exceptional interest because, unlike the previously characterized µ-conotoxin GIIIA (µ-GIIIA), it irreversibly blocks amphibian muscle Na channels, providing a useful tool for synaptic electrophysiology. Furthermore, the discovery of µ-PIIIA permits the resolution of tetrodotoxin-sensitive sodium channels into three categories: (1) sensitive to µ-PIIIA and µ-conotoxin GIIIA, (2) sensitive to µ-PIIIA but not to µ-GIIIA, and (3) resistant to µ-PIIIA and µ-GIIIA (examples in each category are skeletal muscle, rat brain Type II, and many mammalian CNS subtypes, respectively). Thus, µ-conotoxin PIIIA provides a key for further discriminating pharmacologically among different sodium channel subtypes.
Key words: Na channels; µ-conotoxin; tetrodotoxin; neuromuscular transmission; ion channel subtype; peptide
Copyright © 1998 Society for Neuroscience 0270-6474/98/18124473-09$05.00/0
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