The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity.

ABSTRACT: Voltage-gated sodium (Na_V) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe β/δ-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal Na_V channels inhibiting peak current of hNa_V1.1, rNa_V1.2, hNa_V1.6, and hNa_V1.7 while concurrently inhibiting fast inactivation of hNa_V1.1 and rNa_V1.3. The DII and DIV S3-S4 loops of Na_V channel voltage sensors are important for the interaction of Pre1a with Na_V channels but cannot account for its unique subtype selectivity. Through analysis of the binding regions we ascertained that the variability of the S1-S2 loops between Na_V channels contributes substantially to the selectivity profile observed for Pre1a, particularly with regards to fast inactivation. A serine residue on the DIV S2 helix was found to be sufficient to explain Pre1a's potent and selective inhibitory effect on the fast inactivation process of Na_V1.1 and 1.3. This work highlights that interactions with both S1-S2 and S3-S4 of Na_V channels may be necessary for functional modulation, and that targeting the diverse S1-S2 region within voltage-sensing domains provides an avenue to develop subtype selective tools.

SUBMITTER: Wingerd JS 

PROVIDER: S-EPMC5430537 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature