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Published May 3, 2017 | public
Journal Article Open

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_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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© 2017 the authors. Beginning six months after publication the Work will be made freely available to the public on SfN's website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/). Received: 11 August 2016; Revised: 23 March 2017; Accepted: 27 March 2017; Published: 31 March 2017. This work is supported by grants from the National Institutes of Health (DC009433, NS084190 to A.L.; NS17660 and NS 028710 to M.B.K.; MH063232 to R.J.C.), a Carver Research Program of Excellence Award to A.L.; the American Heart Association (14PRE18420020) XW; Austrian Science Fund (FWF) P24079 and F4415 to G.J.O; the G and B. Moore Foundation, and HHMI to M.B.K. We thank J. Hell for providing cDNAs and M. Joiner and other members of the Lee and Colbran Labs for valuable input. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies. Author contributions: S.W., R.S., X.W., G.J.O., and A.L. designed research; S.W., R.S., and X.W. performed research; S.W., R.S., X.W., and G.J.O. analyzed data; S.W. and A.L. wrote the paper; J.H., M.B.K., and R.J.C. contributed unpublished reagents/analytic tools. The authors declare no competing financial interests.

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August 19, 2023
August 19, 2023