A novel mechanism for Ca2+/calmodulin-dependent protein kinase II targeting to L-type Ca2+ channels that initiates long-range signaling to the nucleus

J Biol Chem. 2017 Oct 20;292(42):17324-17336. doi: 10.1074/jbc.M117.788331. Epub 2017 Sep 15.


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Calcium Channels
  • Cacna1d protein, rat
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2

Associated data

  • PDB/3SOA
  • PDB/2WEL