Dataset Information

R-type voltage-gated Ca²⁺ channels mediate A-type K⁺ current regulation of synaptic input in hippocampal dendrites.

ABSTRACT: The subthreshold voltage-gated transient K⁺ current (I_A) carried by pore-forming Kv4.2 subunits regulates the propagation of synaptic input, dendritic excitability, and synaptic plasticity in CA1 pyramidal neuron dendrites of the hippocampus. We report that the Ca²⁺ channel subunit Cav2.3 regulates I_A in this cell type. We initially identified Cav2.3 as a Kv4.2-interacting protein in a proteomic screen and we confirmed Cav2.3-Kv4.2 complex association using multiple techniques. Functionally, Cav2.3 Ca²⁺-entry increases Kv4.2-mediated whole-cell current due to an increase in Kv4.2 surface expression. Using pharmacology and Cav2.3 knockout mice, we show that Cav2.3 regulates the dendritic gradient of I_A. Furthermore, the loss of Cav2.3 function leads to the enhancement of AMPA receptor-mediated synaptic currents and NMDA receptor-mediated spine Ca²⁺ influx. These results propose that Cav2.3 and Kv4.2 are integral constituents of an ion channel complex that affects synaptic function in the hippocampus.

SUBMITTER: Murphy JG

PROVIDER: S-EPMC10496648 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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R-type voltage-gated Ca2+ channels mediate A-type K+ current regulation of synaptic input in hippocampal dendrites.

Murphy Jonathan G JG Gutzmann Jakob J JJ Lin Lin L Hu Jiahua J Petralia Ronald S RS Wang Ya-Xian YX Hoffman Dax A DA

Cell reports 20220101 3

The subthreshold voltage-gated transient K+ current (IA) carried by pore-forming Kv4.2 subunits regulates the propagation of synaptic input, dendritic excitability, and synaptic plasticity in CA1 pyramidal neuron dendrites of the hippocampus. We report that the Ca2+ channel subunit Cav2.3 regulates IA in this cell type. We initially identified Cav2.3 as a Kv4.2-interacting protein in a proteomic screen and we confirmed Cav2.3-Kv4.2 complex association ...[more]

PMID: 35045307

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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.

Dataset Information

R-type voltage-gated Ca²⁺ channels mediate A-type K⁺ current regulation of synaptic input in hippocampal dendrites.

Publications

R-type voltage-gated Ca<sup>2+</sup> channels mediate A-type K<sup>+</sup> current regulation of synaptic input in hippocampal dendrites.

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