Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Cav1.2 Ca2+ Channels at Excitatory Synapses

Voltage-gated Ca(v)1.2 and Ca(v)1.3 (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(v)1.3 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(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.