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Bio-inspired voltage-dependent calcium channel blockers

Author

Listed:
  • Tingting Yang

    (Columbia University, College of Physicians and Surgeons)

  • Lin-Ling He

    (Columbia University, College of Physicians and Surgeons)

  • Ming Chen

    (Columbia University, College of Physicians and Surgeons)

  • Kun Fang

    (Columbia University, College of Physicians and Surgeons)

  • Henry M. Colecraft

    (Columbia University, College of Physicians and Surgeons)

Abstract

Ca2+ influx via voltage-dependent CaV1/CaV2 channels couples electrical signals to biological responses in excitable cells. CaV1/CaV2 channel blockers have broad biotechnological and therapeutic applications. Here we report a general method for developing novel genetically encoded calcium channel blockers inspired by Rem, a small G-protein that constitutively inhibits CaV1/CaV2 channels. We show that diverse cytosolic proteins (CaVβ, 14-3-3, calmodulin and CaMKII) that bind pore-forming α1-subunits can be converted into calcium channel blockers with tunable selectivity, kinetics and potency, simply by anchoring them to the plasma membrane. We term this method ‘channel inactivation induced by membrane-tethering of an associated protein’ (ChIMP). ChIMP is potentially extendable to small-molecule drug discovery, as engineering FK506-binding protein into intracellular sites within CaV1.2-α1C permits heterodimerization-initiated channel inhibition with rapamycin. The results reveal a universal method for developing novel calcium channel blockers that may be extended to develop probes for a broad cohort of unrelated ion channels.

Suggested Citation

  • Tingting Yang & Lin-Ling He & Ming Chen & Kun Fang & Henry M. Colecraft, 2013. "Bio-inspired voltage-dependent calcium channel blockers," Nature Communications, Nature, vol. 4(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3540
    DOI: 10.1038/ncomms3540
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