2. Academic Validation
  3. Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking

Small-molecule CaVα1⋅CaVβ 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.
Xingjuan Chen 1,  Degang Liu 2,  Donghui Zhou 2,  Yubing Si 2,  David Xu 3 4,  Christopher W Stamatkin 1 2,  Mona K Ghozayel 2,  Matthew S Ripsch 5,  Alexander G Obukhov 6 7,  Fletcher A White 8 7,  Samy O Meroueh 9 3 7
Affiliations

Affiliations

  • 1 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202.
  • 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202.
  • 3 Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202.
  • 4 Department of BioHealth Informatics, Indiana University School of Medicine, Indianapolis, IN 46202.
  • 5 Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN 46202.
  • 6 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202; aobukhov@iu.edu fawhite@iu.edu smeroueh@iu.edu.
  • 7 Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202.
  • 8 Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN 46202; aobukhov@iu.edu fawhite@iu.edu smeroueh@iu.edu.
  • 9 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; aobukhov@iu.edu fawhite@iu.edu smeroueh@iu.edu.
PMID: 30355767 DOI: 10.1073/pnas.1813157115
Abstract

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.

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