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

Abstract

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.

Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction

“…Notably, knock-in point mutations in GluN2B that disrupt activity-dependent CaMKII binding in mice significantly reduce CaMKII targeting to PSDs, and impair both synaptic plasticity and memory recall in the Morris Water Maze (Halt et al, 2012). Therefore, we posit that Shank3 may target only a distinct subpopulation of the total postsynaptic CaMKII holoenzymes to specific complexes, consistent with the known roles of Shank3 as a modular synaptic scaffolding protein (Wang et al, 2019).…”

Genetic silencing of striatal CaV1.3 prevents and ameliorates levodopa dyskinesia

“…Although beyond the scope of this report to detail such potential mechanisms, it is clear that there are adaptations in MSNs unrelated to dendritic spine density that may impact LID in the presence of CaV1.3 silencing. Specifically, these channels are linked directly to signaling cascades that not only impact, for example, long‐term alterations in synaptic strength and short‐term dendritic excitability, but also impact synaptic function through selective signaling to the nucleus altering transcriptional activity (eg, references ). The loss of DA tone (specifically D2 receptor tone) after DA depletion disinhibits CaV1.3 channels, leading to structural (eg, spine retraction, synaptic pruning) and functional adaptations .…”

Synapse-to-Nucleus Communication through NFAT Is Mediated by L-type Ca2+ Channel Ca2+ Spike Propagation to the Soma

“…Many nuclear signaling pathways depend critically on Ca 2+ influx through L-type Ca 2+ channels (LTCCs), which have a privileged role among voltage-gated Ca 2+ channels in nuclear signaling ( Ch’ng et al, 2012 ; Graef et al, 1999 ; Wang et al, 2017 ; Wheeler et al, 2012 ). Here, we focused our investigation on synapse-to-nucleus communication through the transcription factor nuclear-factor of activated T cells (NFAT) c3, one of four Ca 2+ -sensitive NFAT isoforms (NFATc1-c4) that has an important, yet not fully understood role in nervous system development and function ( Kipanyula et al, 2016 ).…”