Small-molecule CaVα1·CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking

Xingjuan Chen, Degang Liu, Donghui Zhou, Yubing Si, David Xu, Christopher W. Stamatkin, Mona K. Ghozayel, Matthew S. Ripsch, Alexander Obukhov, Fletcher White, Samy Meroueh

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E10566-E10575
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number45
DOIs
StatePublished - Nov 6 2018

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Calcium Channels
Proteins
Cell Membrane
Nociceptors
Neuralgia
Site-Directed Mutagenesis
Nervous System Diseases
Ion Channels
Analgesia
Action Potentials
Neurotransmitter Agents
Rodentia
Salts
Calcium
Pain

Keywords

  • Calcium channel
  • Pain
  • Protein-protein interactions
  • Small-molecule inhibitors
  • β subunit

ASJC Scopus subject areas

  • General

Cite this

Small-molecule CaVα1·CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking. / Chen, Xingjuan; Liu, Degang; Zhou, Donghui; Si, Yubing; Xu, David; Stamatkin, Christopher W.; Ghozayel, Mona K.; Ripsch, Matthew S.; Obukhov, Alexander; White, Fletcher; Meroueh, Samy.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 45, 06.11.2018, p. E10566-E10575.

Research output: Contribution to journalArticle

Chen, Xingjuan ; Liu, Degang ; Zhou, Donghui ; Si, Yubing ; Xu, David ; Stamatkin, Christopher W. ; Ghozayel, Mona K. ; Ripsch, Matthew S. ; Obukhov, Alexander ; White, Fletcher ; Meroueh, Samy. / Small-molecule CaVα1·CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 45. pp. E10566-E10575.
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AB - 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.

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