TY - JOUR
AU - Bulaj, Grzegorz
AB - <p>Peptide neurotoxins from cone snails continue to supply compounds with therapeutic potential. Although several analgesic conotoxins have already reached human clinical trials, a continuing need exists for the discovery and development of novel non-opioid analgesics, such as subtype-selective sodium channel blockers. μ-Conotoxin KIIIA is representative of μ-conopeptides previously characterized as inhibitors of tetrodotoxin (TTX)-resistant sodium channels in amphibian dorsal root ganglion neurons. Here, we show that KIIIA has potent analgesic activity in the mouse pain model. Surprisingly, KIIIA was found to block most (>80%) of the TTX-sensitive, but only ∼20% of the TTX-resistant, sodium current in mouse dorsal root ganglion neurons. KIIIA was tested on cloned mammalian channels expressed in <i>Xenopus</i> oocytes. Both Na<sub>V</sub>1.2 and Na<sub>V</sub>1.6 were strongly blocked; within experimental wash times of 40–60 min, block was reversed very little for Na<sub>V</sub>1.2 and only partially for Na<sub>V</sub>1.6. Other isoforms were blocked reversibly: Na<sub>V</sub>1.3 (IC<sub>50</sub> 8 μm), Na<sub>V</sub>1.5 (IC<sub>50</sub> 284 μm), and Na<sub>V</sub>1.4 (IC<sub>50</sub> 80 nm). "Alanine-walk" and related analogs were synthesized and tested against both Na<sub>V</sub>1.2 and Na<sub>V</sub>1.4; replacement of Trp-8 resulted in reversible block of Na<sub>V</sub>1.2, whereas replacement of Lys-7, Trp-8, or Asp-11 yielded a more profound effect on the block of Na<sub>V</sub>1.4 than of Na<sub>V</sub>1.2. Taken together, these data suggest that KIIIA is an effective tool to study structure and function of Na<sub>V</sub>1.2 and that further engineering of μ-conopeptides belonging to the KIIIA group may provide subtype-selective pharmacological compounds for mammalian neuronal sodium channels and potential therapeutics for the treatment of pain.</p>
TI - Structure/Function Characterization of μ-Conotoxin KIIIA, an Analgesic, Nearly Irreversible Blocker of Mammalian Neuronal Sodium Channels *
JF - Journal of Biological Chemistry
DO - 10.1074/jbc.m704616200
DA - 2007-10-19
UR - https://www.deepdyve.com/lp/american-society-for-biochemistry-and-molecular-biology/structure-function-characterization-of-conotoxin-kiiia-an-analgesic-lxO6ECf98n
SP - 30699
EP - 30706
VL - 282
IS - 42
DP - DeepDyve
ER -