Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Ca v 1.2 Ca 2+ Channels at Excitatory Synapses.

Voltage-gated Ca _v 1.2 and Ca _v 1.3 (L-type) Ca ²⁺ channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca ²⁺ -dependent facilitation of voltage-gated Ca _v 1.3 Ca ²⁺ 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 Ca _v 1.2 than Ca _v 1.3. Therefore, we investigated the functional impact of densin on Ca _v 1.2. We report that densin is an essential regulator of Ca _v 1.2 in neurons, but has distinct modulatory effects compared with its regulation of Ca _v 1.3. Densin binds to the N-terminal domain of Ca _v 1.2, but not that of Ca _v 1.3, and increases Ca _v 1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Ca _v 1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Ca _v 1.2 channels, overexpression of densin increases the clustering of Ca _v 1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Ca _v 1.2 in the brain, as well as Ca _v 1.2 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 Ca _v 1 channels and ensures efficient Ca _v 1.2 Ca ²⁺ signaling at excitatory synapses. SIGNIFICANCE STATEMENT The number and localization of voltage-gated Ca _v Ca ²⁺ 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 Ca _v 1.2 L-type Ca ²⁺ channels in neurons. This interaction promotes coupling of Ca _v 1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Ca _v 1.2 in regulating cognition and mood.
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