Journal of Biological Chemistry
Volume 292, Issue 42, 20 October 2017, Pages 17324-17336
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Neurobiology
A novel mechanism for Ca2+/calmodulin-dependent protein kinase II targeting to L-type Ca2+ channels that initiates long-range signaling to the nucleus

https://doi.org/10.1074/jbc.M117.788331Get rights and content
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Neuronal excitation can induce new mRNA transcription, a phenomenon called excitation–transcription (E-T) coupling. Among several pathways implicated in E-T coupling, activation of voltage-gated L-type Ca2+ channels (LTCCs) in the plasma membrane can initiate a signaling pathway that ultimately increases nuclear CREB phosphorylation and, in most cases, expression of immediate early genes. Initiation of this long-range pathway has been shown to require recruitment of Ca2+-sensitive enzymes to a nanodomain in the immediate vicinity of the LTCC by an unknown mechanism. Here, we show that activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) strongly interacts with a novel binding motif in the N-terminal domain of CaV1 LTCC α1 subunits that is not conserved in CaV2 or CaV3 voltage-gated Ca2+ channel subunits. Mutations in the CaV1.3 α1 subunit N-terminal domain or in the CaMKII catalytic domain that largely prevent the in vitro interaction also disrupt CaMKII association with intact LTCC complexes isolated by immunoprecipitation. Furthermore, these same mutations interfere with E-T coupling in cultured hippocampal neurons. Taken together, our findings define a novel molecular interaction with the neuronal LTCC that is required for the initiation of a long-range signal to the nucleus that is critical for learning and memory.

Ca2+/calmodulin-dependent protein kinase II (CaMKII)
calcium channel
cAMP-response element-binding protein (CREB)
neuron
protein-protein interaction

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This work was supported in part by National Institutes of Health Grants R01-MH063232 and R01-NS078291 (to R. J. C.), R01-DK097392 (to D. A. J.), R01-DC009433 and R01-NS084190 (to A. L.), R01-HD061543 (to T. N.), and F31-MH109196 (to C. R. M.) and American Heart Association predoctoral fellowships 14PRE18420020 (to X. W.) and 15PRE25110020 (to C. R. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

1

Supported by National Institutes of Health Grant T32-DK07563.

2

Supported by American Diabetes Association Grant 1-17-IBS-024.