PT  - JOURNAL ARTICLE
AU  - Shiyi Wang
AU  - Ruslan I. Stanika
AU  - Xiaohan Wang
AU  - Jussara Hagen
AU  - Mary B. Kennedy
AU  - Gerald J. Obermair
AU  - Roger J. Colbran
AU  - Amy Lee
TI  - Densin-180 controls the trafficking and signaling of L-type voltage-gated Ca<sub>v</sub>1.2 Ca<sup>2+</sup> channels at excitatory synapses
AID  - 10.1523/JNEUROSCI.2583-16.2017
DP  - 2017 Mar 31
TA  - The Journal of Neuroscience
PG  - 2583-16
4099  - http://www.jneurosci.org/content/early/2017/03/31/JNEUROSCI.2583-16.2017.short
4100  - http://www.jneurosci.org/content/early/2017/03/31/JNEUROSCI.2583-16.2017.full
AB  - 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. Thus, 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 to its regulation of Cav1.3. Densin binds to the N-terminal domain of Cav1.2 but not 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 to 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 Cav Ca2+ channels are crucial determinants of neuronal excitability and synaptic transmission. We report that a protein that is highly enriched at excitatory synapses in the brain, densin-180, 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.