A novel mechanism for Ca/calmodulin-dependent protein kinase II targeting to L-type Ca channels that initiates long-range signaling to the nucleus.

Wang X, Marks CR, Perfitt TL, Nakagawa T, Lee A, Jacobson DA, Colbran RJ
J Biol Chem. 2017 292 (42): 17324-17336

PMID: 28916724 · PMCID: PMC5655510 · DOI:10.1074/jbc.M117.788331

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 Ca 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 Ca-sensitive enzymes to a nanodomain in the immediate vicinity of the LTCC by an unknown mechanism. Here, we show that activated Ca/calmodulin-dependent protein kinase II (CaMKII) strongly interacts with a novel binding motif in the N-terminal domain of Ca1 LTCC α1 subunits that is not conserved in Ca2 or Ca3 voltage-gated Ca channel subunits. Mutations in the Ca1.3 α1 subunit N-terminal domain or in the CaMKII catalytic domain that largely prevent the 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.

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (13)

Animals Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calcium Channels Cell Nucleus Female Hippocampus Learning Memory Neurons Protein Domains Rats Rats, Sprague-Dawley Signal Transduction

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