A potent voltage-gated calcium channel inhibitor engineered from a nanobody targeted to auxiliary Ca_Vβ subunits.

ABSTRACT: Inhibiting high-voltage-activated calcium channels (HVACCs; Ca_V1/Ca_V2) is therapeutic for myriad cardiovascular and neurological diseases. For particular applications, genetically-encoded HVACC blockers may enable channel inhibition with greater tissue-specificity and versatility than is achievable with small molecules. Here, we engineered a genetically-encoded HVACC inhibitor by first isolating an immunized llama nanobody (nb.F3) that binds auxiliary HVACC Ca_Vβ subunits. Nb.F3 by itself is functionally inert, providing a convenient vehicle to target active moieties to Ca_Vβ-associated channels. Nb.F3 fused to the catalytic HECT domain of Nedd4L (Ca_V-aβlator), an E3 ubiquitin ligase, ablated currents from diverse HVACCs reconstituted in

SUBMITTER: Morgenstern TJ 

PROVIDER: S-EPMC6701945 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature