- Wang X, Marks CR, Perfitt TL, Nakagawa T, Lee A, Jacobson DA, Colbran RJ. A novel mechanism for Ca(2+)/calmodulin-dependent protein kinase II targeting to L-type Ca(2+) channels that initiates long-range signaling to the nucleus. The Journal of biological chemistry. 2017 Sep 15. PMID: 28916724 [PubMed].
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(2+) 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(2+)-sensitive enzymes to a nanodomain in the immediate vicinity of the LTCC by an unknown mechanism. Here, we show that activated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) strongly interacts with a novel binding motif in the N-terminal domain (NTD) of CaV1 LTCC α1 subunits that is not conserved in CaV2 or CaV3 voltage-gated Ca(2+) channel subunits. Mutations in the CaV1.3 α1 subunit NTD 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.