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Small-molecule CaV?1?CaV? antagonist suppresses neuronal voltage-gated calcium-channel trafficking.

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 ?1 subunit (CaV?1) that is engaged in protein-protein interactions with auxiliary ?2/? and ? subunits. The high-affinity CaV2.2?1?CaV?3 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 CaV2.2?1?CaV?3 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 ?-helix of CaV2.2?1 Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaV?3 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 ?-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.

SUBMITTER: Chen X

PROVIDER: S-EPMC6233087 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Chen Xingjuan X Liu Degang D Zhou Donghui D Si Yubing Y Xu David D Stamatkin Christopher W CW Ghozayel Mona K MK Ripsch Matthew S MS Obukhov Alexander G AG White Fletcher A FA Meroueh Samy O SO

Proceedings of the National Academy of Sciences of the United States of America 20181024 45

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 ...[more]

PMID: 30355767

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Project description:BackgroundFlavonoids in Chinese Medicine have been proven in animal studies that could aid in osteogenesis and bone formation. However, there is no consented mechanism for how these phytochemicals action on the bone-forming osteoblasts, and henceforth the prediction model of chemical screening for this specific biochemical function has not been established. The purpose of this study was to develop a novel selection and effective approach of flavonoids on the prediction of bone-forming ability via osteoblastic voltage-gated calcium (CaV) activation and inhibition using molecular modelling technique.MethodQuantitative structure-activity relationship (QSAR) in supervised maching-learning approach is applied in this study to predict the behavioral manifestations of flavonoids in the CaV channels, and developing statistical correlation between the biochemical features and the behavioral manifestations of 24 compounds (Training set: Kaempferol, Taxifolin, Daidzein, Morin, Scutellarein, Quercetin, Apigenin, Myricetin, Tamarixetin, Rutin, Genistein, 5,7,2'-Trihydroxyflavone, Baicalein, Luteolin, Galangin, Chrysin, Isorhamnetin, Naringin, 3-Methyl galangin, Resokaempferol; test set: 5-Hydroxyflavone, 3,6,4'-Trihydroxyflavone, 3,4'-Dihydroxyflavone and Naringenin). Based on statistical algorithm, QSAR provides a reasonable basis for establishing a predictive correlation model by a variety of molecular descriptors that are able to identify as well as analyse the biochemical features of flavonoids that engaged in activating or inhibiting the CaV channels for osteoblasts.ResultsThe model has shown these flavonoids have high activating effects on CaV channel for osteogenesis. In addition, scutellarein was ranked the highest among the screened flavonoids, and other lower ranked compounds, such as daidzein, quercetin, genistein and naringin, have shown the same descending order as previous animal studies.ConclusionThis predictive modelling study has confirmed and validated the biochemical activity of the flavonoids in the osteoblastic CaV activation.

Dataset Information

Small-molecule CaV?1?CaV? antagonist suppresses neuronal voltage-gated calcium-channel trafficking.

Publications

Small-molecule Ca<sub>V</sub>α<sub>1</sub>⋅Ca<sub>V</sub>β antagonist suppresses neuronal voltage-gated calcium-channel trafficking.

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