Densin-180 controls the trafficking and signaling of L-type voltage-gated Ca_v 1.2 Ca^(2+) channels at excitatory synapses

Abstract

Voltage-gated Ca_v1.2 and Ca_v1.3 (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_v1.3 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_v1.2 than Ca_v1.3. Thus, 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 to its regulation of Ca_v1.3. Densin binds to the N-terminal domain of Ca_v1.2 but not 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 to 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 Ca^(2+) signaling at excitatory synapses.

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