Voltage-gated Ca1.2 and Ca1.3 (L-type) Ca channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca-dependent facilitation of voltage-gated Ca1.3 Ca 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 Ca1.2 than Ca1.3. Therefore, we investigated the functional impact of densin on Ca1.2. We report that densin is an essential regulator of Ca1.2 in neurons, but has distinct modulatory effects compared with its regulation of Ca1.3. Densin binds to the N-terminal domain of Ca1.2, but not that of Ca1.3, and increases Ca1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Ca1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Ca1.2 channels, overexpression of densin increases the clustering of Ca1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Ca1.2 in the brain, as well as Ca1.2 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 Ca1 channels and ensures efficient Ca1.2 Ca signaling at excitatory synapses. The number and localization of voltage-gated Ca Ca 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 Ca1.2 L-type Ca channels in neurons. This interaction promotes coupling of Ca1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Ca1.2 in regulating cognition and mood.
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