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 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.
Highlights
Neuronal excitation can induce new mRNA transcription, a phenomenon called excitation–transcription (E-T) coupling
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 L-type Ca2؉ channels (LTCCs) ␣1 subunits that is not conserved in CaV2 or CaV3 voltage-gated Ca2؉ channel subunits
Our data identify a novel CaMKII binding site in the N-terminal domain (NTD) of LTCCs that is important for the coupling of LTCCs to a nuclear response
Summary
CaMKII has been suggested to interact with the pore-forming ␣1 subunits of CaV1.2 and CaV1.3 LTCCs [17,18,19,20], there are conflicting data about the specific domains involved. There was no consistently detectable binding of inactive CaMKII to any of the intracellular domains above the level of GST control, but the CaV1.3 NTD directly and interacts with activated CaMKII conformations induced by pre-autophosphorylation at Thr-286 (Fig. 1B) or by the binding of Ca2ϩ/calmodulin and ADP (Fig. 1C). The fact that binding of Ca2ϩ/calmodulin and ADP to CaMKII is sufficient to induce interaction with the NTD shows that Thr-286 phosphorylation is not necessary for binding; rather, an open, activated conformation of CaMKII is required. These data show that activated CaMKII directly interacts with the NTD of CaV1.3 with very high selectivity
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