Recombinant Thrixopelma pruriens Beta/omega-theraphotoxin-Tp2a

Gating-modifier toxin that targets voltage-gated sodium channels with a selective activity on Nav1.7/SCN9A (IC(50)=1-1.5 nM). It inhibits both activation and inactivation. For inhibition of activation, it is 100-fold more selective for Nav1.7/SCN9A (IC(50)=0.26-3) than for other sodium channels (Nav1.2/SCN2A (IC(50)=40-540 nM), Nav1.3/SCN3A (IC(50)=102 nM), Nav1.4/SCN4A (IC(50)=30-39 nM), Nav1.5/SCN5A (IC(50)=19-90 nM), Nav1.6/SCN8A (IC(50)=26 nM), and Nav1.8/SCN10A (IC(50)=146 nM)). For inhibition of inactivation, it is 20-fold more potent in inhibiting inactivation on Nav1.7/SCN9A (IC(50)=250 nM) than other channels (about 4.6 uM for all channels). It also weakly inhibits Cav1.2/CACNA1C and Cav3.2/CACNA1H (29% block at 1 uM). It inhibits Nav1.7/SCN9A activation by interacting with DII and impairs Nav1.7/SCN9A inactivation by interacting with DIV. It docks on top of the DII S3 helix Nav1.7/SCN9A. It is about 60-fold less active on Nav1.7/SCN9A at depolarized potential (0 mV; IC(50)=15 nM), compared to -120 mV potential (IC(50)=0.26 nM). This toxin binds to lipid membrane. This ability correlates with hNav1.7/SCN9A inhibition, showing that membrane binding is the first step in the inhibitory mechanism of this toxin. It inhibits Nav1.2/SCN2A less potently when it is coexpressed with SCN2B or SCN4B than when it is expressed alone, showing that beta subunits (SCN2B and SCN4B) have a protective effect.