Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Rosker, C; Lohberger, B; Hofer, D; Steinecker, B; Quasthoff, S; Schreibmayer, W.
The TTX metabolite 4,9-anhydro-TTX is a highly specific blocker of the Na(v1.6) voltage-dependent sodium channel.
Am J Physiol Cell Physiol. 2007; 293(2): C783-C789.
Doi: 10.1152/ajpcell.00070.2007
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- Führende Autor*innen der Med Uni Graz
- Rosker Christian
- Schreibmayer Wolfgang
- Co-Autor*innen der Med Uni Graz
- Hofer Doris
- Lohberger Birgit
- Quasthoff Stefan
- Steinecker-Frohnwieser Bibiane
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- Abstract:
- The blocking efficacy of 4,9-anhydro-TTX (4,9-ah-TTX) and TTX on several isoforms of voltage-dependent sodium channels, expressed in Xenopus laevis oocytes, was tested (Na(v1.2), Na(v1.3), Na(v1.4), Na(v1.5), Na(v1.6), Na(v1.7), and Na(v1.8)). Generally, TTX was 40-231 times more effective, when compared with 4,9-ah-TTX, on a given isoform. An exception was Na(v1.6), where 4,9-ah-TTX in nanomole per liter concentrations sufficed to result in substantial block, indicating that 4,9-ah-TTX acts specifically at this peculiar isoform. The IC(50) values for TTX/4,9-ah-TTX were as follows (in nmol/l): 7.8 +/- 1.3/1,260 +/- 121 (Na(v1.2)), 2.8 +/- 2.3/341 +/- 36 (Na(v1.3)), 4.5 +/- 1.0/988 +/- 62 (Na(v1.4)), 1,970 +/- 565/78,500 +/- 11,600 (Na(v1.5)), 3.8 +/- 1.5/7.8 +/- 2.3 (Na(v1.6)), 5.5 +/- 1.4/1,270 +/- 251 (Na(v1.7)), and 1,330 +/- 459/>30,000 (Na(v1.8)). Analysis of approximal half-maximal doses of both compounds revealed minor effects on voltage-dependent activation only, whereas steady-state inactivation was shifted to more negative potentials by both TTX and 4,9-ah-TTX in the case of the Na(v1.6) subunit, but not in the case of other TTX-sensitive ones. TTX shifted steady-state inactivation also to more negative potentials in case of the TTX-insensitive Na(v1.5) subunit, where it also exerted profound effects on the time course of recovery from inactivation. Isoform-specific interaction of toxins with ion channels is frequently observed in the case of proteinaceous toxins. Although the sensitivity of Na(v1.1) to 4,9-ah-TTX is not known, here we report evidence on a highly isoform-specific TTX analog that may well turn out to be an invaluable tool in research for the identification of Na(v1.6)-mediated function, but also for therapeutic intervention.
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- Animals -
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- Membrane Potentials - drug effects
- Mice - drug effects
- Microinjections - drug effects
- Muscle Proteins - metabolism
- Nerve Tissue Proteins - drug effects
- Oocytes - drug effects
- Rats - drug effects
- Sodium - metabolism
- Sodium Channel Blockers - metabolism
- Sodium Channels - drug effects
- Tetrodotoxin - analogs and derivatives
- Xenopus laevis - analogs and derivatives
- Find related publications in this database (Keywords)
- sodium channel
- tetrodotoxin