Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Ca_v1.2 Ca²⁺ Channels at Excitatory Synapses

Voltage-gated Ca_v1.2 and Ca_v1.3 (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 Ca_v1.3 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 Ca_v1.2 than Ca_v1.3. Therefore, we investigated the functional impact of densin on Ca_v1.2. We report that densin is an essential regulator of Ca_v1.2 in neurons, but has distinct modulatory effects compared with its regulation of Ca_v1.3. Densin binds to the N-terminal domain of Ca_v1.2, but not that of Ca_v1.3, and increases Ca_v1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Ca_v1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Ca_v1.2 channels, overexpression of densin increases the clustering of Ca_v1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Ca_v1.2 in the brain, as well as Ca_v1.2 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_v1 channels and ensures efficient Ca_v1.2 Ca²⁺ signaling at excitatory synapses.SIGNIFICANCE STATEMENT The number and localization of voltage-gated Ca_v 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 Ca_v1.2 L-type Ca²⁺ channels in neurons. This interaction promotes coupling of Ca_v1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Ca_v1.2 in regulating cognition and mood.