| Summary: | The 27-amino acid (aa)-long δ-conotoxin TxVIA, originally isolated from the mollusc-hunting cone snail <i>Conus textile</i>, slows voltage-gated sodium (Na<sub>V</sub>) channel inactivation in molluscan neurons, but its mammalian ion channel targets remain undetermined. In this study, we confirmed that TxVIA was inactive on mammalian Na<sub>V</sub>1.2 and Na<sub>V</sub>1.7 even at high concentrations (10 µM). Given the fact that invertebrate Na<sub>V</sub> channel and T-type calcium channels (Ca<sub>V</sub>3.x) are evolutionarily related, we examined the possibility that TxVIA may act on Ca<sub>V</sub>3.x. Electrophysiological characterisation of the native TxVIA on Ca<sub>V</sub>3.1, 3.2 and 3.3 revealed that TxVIA preferentially inhibits Ca<sub>V</sub>3.2 current (IC<sub>50</sub> = 0.24 μM) and enhances Ca<sub>V</sub>3.1 current at higher concentrations. In fish bioassays TxVIA showed little effect on zebrafish behaviours when injected intramuscular at 250 ng/100 mg fish. The binding sites for TxVIA at Na<sub>V</sub>1.7 and Ca<sub>V</sub>3.1 revealed that their channel binding sites contained a common epitope.
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