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An Improved Method for Modeling Voltage-Gated Ion Channels at Atomic Accuracy Applied to Human Ca_v Channels.

ABSTRACT: Voltage-gated ion channels (VGICs) are associated with hundreds of human diseases. To date, 3D structural models of human VGICs have not been reported. We developed a 3D structural integrity metric to rank the accuracy of all VGIC structures deposited in the PDB. The metric revealed inaccuracies in structural models built from recent single-particle, non-crystalline cryo-electron microscopy maps and enabled the building of highly accurate homology models of human Ca_v channel ?₁ subunits at atomic resolution. Human Ca_v Mendelian mutations mostly located to segments involved in the mechanism of voltage sensing and gating within the 3D structure, with multiple mutations targeting equivalent 3D structural locations despite eliciting distinct clinical phenotypes. The models also revealed that the architecture of the ion selectivity filter is highly conserved from bacteria to humans and between sodium and calcium VGICs.

SUBMITTER: Martinez-Ortiz W

PROVIDER: S-EPMC5957504 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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An Improved Method for Modeling Voltage-Gated Ion Channels at Atomic Accuracy Applied to Human Cav Channels.

Martinez-Ortiz Wilnelly W Cardozo Timothy J TJ

Cell reports 20180501 5

Voltage-gated ion channels (VGICs) are associated with hundreds of human diseases. To date, 3D structural models of human VGICs have not been reported. We developed a 3D structural integrity metric to rank the accuracy of all VGIC structures deposited in the PDB. The metric revealed inaccuracies in structural models built from recent single-particle, non-crystalline cryo-electron microscopy maps and enabled the building of highly accurate homology models of human Cav channel α1</ ...[more]

PMID: 29719253

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Project description:Voltage-gated Cav1.2 and Cav1.3 (L-type) Ca2+ channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca2+-dependent facilitation of voltage-gated Cav1.3 Ca2+ channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Cav1.2 than Cav1.3. Therefore, we investigated the functional impact of densin on Cav1.2. We report that densin is an essential regulator of Cav1.2 in neurons, but has distinct modulatory effects compared with its regulation of Cav1.3. Densin binds to the N-terminal domain of Cav1.2, but not that of Cav1.3, and increases Cav1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Cav1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Cav1.2 channels, overexpression of densin increases the clustering of Cav1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Cav1.2 in the brain, as well as Cav1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Cav1 channels and ensures efficient Cav1.2 Ca2+ signaling at excitatory synapses.SIGNIFICANCE STATEMENT The number and localization of voltage-gated Cav Ca2+ channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Cav1.2 L-type Ca2+ channels in neurons. This interaction promotes coupling of Cav1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Cav1.2 in regulating cognition and mood.

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An Improved Method for Modeling Voltage-Gated Ion Channels at Atomic Accuracy Applied to Human Ca_v Channels.

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An Improved Method for Modeling Voltage-Gated Ion Channels at Atomic Accuracy Applied to Human Ca<sub>v</sub> Channels.

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