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

Wang, Shiyi and Stanika, Ruslan I. and Wang, Xiaohan and Hagen, Jussara and Kennedy, Mary B. and Obermair, Gerald J. and Colbran, Roger J. and Lee, Amy (2017) Densin-180 controls the trafficking and signaling of L-type voltage-gated Ca_v 1.2 Ca^(2+) channels at excitatory synapses. Journal of Neuroscience, 37 (18). pp. 4679-4691. ISSN 0270-6474. PMCID PMC5426563. https://resolver.caltech.edu/CaltechAUTHORS:20170410-130729438

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1523/JNEUROSCI.2583-16.2017DOIArticle
http://www.jneurosci.org/content/37/18/4679PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426563/PubMed CentralArticle
ORCID:
AuthorORCID
Wang, Shiyi0000-0003-3433-3025
Wang, Xiaohan0000-0001-7895-2333
Kennedy, Mary B.0000-0003-1369-0525
Colbran, Roger J.0000-0001-7401-8244
Lee, Amy0000-0001-8021-0443
Additional Information:© 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.
Funders:
Funding AgencyGrant Number
NIHDC009433
NIHNS084190
NIHNS17660
NIHNS028710
NIHMH063232
Carver Research Program of Excellence AwardUNSPECIFIED
American Heart Association14PRE18420020
FWF Der WissenschaftsfondsP24079
FWF Der WissenschaftsfondsF4415
Gordon and Betty Moore FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:18
PubMed Central ID:PMC5426563
Record Number:CaltechAUTHORS:20170410-130729438
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170410-130729438
Official Citation:Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Cav1.2 Ca2+ Channels at Excitatory Synapses Shiyi Wang, Ruslan I. Stanika, Xiaohan Wang, Jussara Hagen, Mary B. Kennedy, Gerald J. Obermair, Roger J. Colbran,, Amy Lee Journal of Neuroscience 3 May 2017, 37 (18) 4679-4691; DOI: 10.1523/JNEUROSCI.2583-16.2017
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76478
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Apr 2017 21:05
Last Modified:03 Oct 2019 17:01

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