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Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel
Perfitt TL, Wang X, Dickerson MT, Stephenson JR, Nakagawa T, Jacobson DA,
Submitted Externally on 3/26/2020
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume : Pages
40 : 2000 - 2014
The activation of neuronal plasma membrane Ca2+ channels stimulates many
intracellular responses. Scaffolding proteins can preferentially couple specific
Ca2+ channels to distinct downstream outputs, such as increased gene expression,
but the molecular mechanisms that underlie the exquisite specificity of these
signaling pathways are incompletely understood. Here, we show that complexes
containing CaMKII and Shank3, a postsynaptic scaffolding protein known to
interact with L-type calcium channels (LTCCs), can be specifically
coimmunoprecipitated from mouse forebrain extracts. Activated purified CaMKIIa
also directly binds Shank3 between residues 829 and 1130. Mutation of Shank3
residues 949Arg-Arg-Lys951 to three alanines disrupts CaMKII binding in vitro
and CaMKII association with Shank3 in heterologous cells. Our shRNA/rescue
studies revealed that Shank3 binding to both CaMKII and LTCCs is important for
increased phosphorylation of the nuclear CREB transcription factor and
expression of c-Fos induced by depolarization of cultured hippocampal neurons.
Thus, this novel CaMKII-Shank3 interaction is essential for the initiation of a
specific long-range signal from LTCCs in the plasma membrane to the nucleus that
is required for activity-dependent changes in neuronal gene expression during
learning and memory.SIGNIFICANCE STATEMENT Precise neuronal expression of genes
is essential for normal brain function. Proteins involved in signaling pathways
that underlie activity-dependent gene expression, such as CaMKII, Shank3, and
L-type calcium channels, are often mutated in multiple neuropsychiatric
disorders. Shank3 and CaMKII were previously shown to bind L-type calcium
channels, and we show here that Shank3 also binds to CaMKII. Our data show that
each of these interactions is required for depolarization-induced
phosphorylation of the CREB nuclear transcription factor, which stimulates the
expression of c-Fos, a neuronal immediate early gene with key roles in synaptic
plasticity, brain development, and behavior.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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