Small-molecule Ca V α 1⋅Ca V β antagonist suppresses neuronal voltage-gated calcium-channel trafficking

Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10566-E10575. doi: 10.1073/pnas.1813157115. Epub 2018 Oct 24.


Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1 subunit (CaVα1) that is engaged in protein-protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3 protein-protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3 protein-protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1 Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3 Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein-protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.

Keywords: calcium channel; pain; protein–protein interactions; small-molecule inhibitors; β subunit.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium Channel Blockers / pharmacokinetics
  • Calcium Channel Blockers / pharmacology*
  • Female
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / drug effects*
  • Ion Transport
  • Large-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism
  • Mice
  • Neuralgia / prevention & control
  • Nociception / drug effects
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology*


  • Calcium Channel Blockers
  • Large-Conductance Calcium-Activated Potassium Channels
  • Small Molecule Libraries