Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Ca_v1.2 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.

α-Actinin Promotes Surface Localization and Current Density of the Ca2+ Channel CaV1.2 by Binding to the IQ Region of the α1 Subunit

“…Similarly, binding of the structural protein densin-180 to the N-terminus of α 1 1.2 promotes secretory trafficking of Ca V 1.2 but not its surface retention (65). Thus, a clear understanding of how Ca V 1.2 is anchored at certain locations such as postsynaptic sites in neurons (6, 21) has been elusive until recently.…”

Functional Annotation of the Transcriptome of the Pig, Sus scrofa, Based Upon Network Analysis of an RNAseq Transcriptional Atlas

“…the novel ENSSSCG gene is coexpressed with an annotated gene that corresponds with known human transcript in the expected genomic location based on conservation of synteny). For example, LLRC7, which encodes the excitatory synaptic protein densin-180 (Wang et al, 2017) is expressed in a CNS-specific manner in humans. The pig DNA sequences corresponding to human LLRC7 were annotated as three separate genes in Suscrofa11.1 (Ensembl release 90) all of which are contained within the same genomic region and with the same transcriptional orientation.…”

The Effect of Nitrendipine and Levetiracetam in Pentylenetetrazole Kindled Rats

“…It is known that the voltage-gated channels regulate intracellular signaling pathways, such as neurotransmitter release by affecting calcium influx [34] . L-type voltage-gated calcium channels are crucial for neuronal excitability and synaptic transmission [35] . In dorsal root ganglion neurons from rats L-type voltagegated calcium channel blocker nitrendipine inhibits GABA-activated currents.…”