title: Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Cav1.2 Ca2+Channels at Excitatory Synapses.
abstract: 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 STATEMENTThe number and localization of voltage-gated CavCa2+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.
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Shiyi
authors.identifier: 0000-0003-3433-3025
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Physiology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Stanika
authors.affiliation: Department of Molecular Physiology and Biophysics and the Brain Institute, Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Xiaohan
authors.identifier: 0000-0001-7895-2333
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Jussara
authors.initials: J
authors.lastname: Hagen
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, California 91125.
authors.forename: Mary B
authors.identifier: 0000-0003-1369-0525
authors.initials: MB
authors.lastname: Kennedy
authors.affiliation: Division of Physiology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Obermair
authors.affiliation: Department of Molecular Physiology and Biophysics and the Brain Institute, Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: Roger J
authors.identifier: 0000-0001-7401-8244
authors.initials: RJ
authors.lastname: Colbran
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, amy-lee@uiowa.edu.|Department of Otolaryngology Head-Neck Surgery, University of Iowa, Iowa City, Iowa 52242, and.|Department of Neurology, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Amy
authors.identifier: 0000-0001-8021-0443
authors.initials: A
authors.lastname: Lee
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002540:Cerebral Cortex / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D012795:Sialoglycoproteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; C504462:Lrrc7 protein, mouse; D012795:Sialoglycoproteins
keywords: excitatory; postsynaptic; trafficking