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Memory reconsolidation and its maintenance depend on L-voltage-dependent calcium channels and CaMKII functions regulating protein turnover in the hippocampus.

ABSTRACT: Immediate postretrieval bilateral blockade of long-acting voltage-dependent calcium channels (L-VDCCs), but not of glutamatergic NMDA receptors, in the dorsal CA1 region of the hippocampus hinders retention of long-term spatial memory in the Morris water maze. Immediate postretrieval bilateral inhibition of calcium/calmodulin-dependent protein kinase (CaMK) II in dorsal CA1 does not affect retention of this task 24 h later but does hinder it 5 d later. These two distinct amnesic effects are abolished if protein degradation by proteasomes is inhibited concomitantly. These results indicate that spatial memory reconsolidation depends on the functionality of L-VDCC in dorsal CA1, that maintenance of subsequent reconsolidated memory trace depends on CaMKII, and these results also suggest that the role played by both L-VDCC and CaMKII is to promote the retrieval-dependent, synaptically localized enhancement of protein synthesis necessary to counteract a retrieval-dependent, synaptic-localized enhancement of protein degradation, which has been described as underlying the characteristic labilization of the memory trace triggered by retrieval. Thus, conceivably, L-VDCC and CaMKII would enhance activity-dependent localized protein renewal, which may account for the improvement of the long-term efficiency of the synapses responsible for the maintenance of reactivated long-term spatial memory.

SUBMITTER: Da Silva WC

PROVIDER: S-EPMC3631664 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Memory reconsolidation and its maintenance depend on L-voltage-dependent calcium channels and CaMKII functions regulating protein turnover in the hippocampus.

Da Silva Weber Cláudio WC Cardoso Gabriela G Bonini Juliana Sartori JS Benetti Fernando F Izquierdo Ivan I

Proceedings of the National Academy of Sciences of the United States of America 20130401 16

Immediate postretrieval bilateral blockade of long-acting voltage-dependent calcium channels (L-VDCCs), but not of glutamatergic NMDA receptors, in the dorsal CA1 region of the hippocampus hinders retention of long-term spatial memory in the Morris water maze. Immediate postretrieval bilateral inhibition of calcium/calmodulin-dependent protein kinase (CaMK) II in dorsal CA1 does not affect retention of this task 24 h later but does hinder it 5 d later. These two distinct amnesic effects are abol ...[more]

PMID: 23576750

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Project description:Neuronal excitation-transcription (E-T) coupling pathways can be initiated by local increases of Ca2+ concentrations within a nanodomain close to the L-type voltage-gated Ca2+ channel (LTCC). However, molecular mechanisms controlling LTCC organization within the plasma membrane that help creation these localized signaling domains remain poorly characterized. Here, we report that neuronal depolarization increases CaV1.3 LTCC clustering in cultured hippocampal neurons. Our previous work showed that binding of the activated catalytic domain of Ca2+/calmodulin-dependent protein kinase II (CaMKII) to an RKR motif in the N-terminal cytoplasmic domain of CaV1.3 is required for LTCC-mediated E-T coupling. We tested whether multimeric CaMKIIα holoenzymes can bind simultaneously to co-expressed CaV1.3 α1 subunits with two different epitope tags. Co-immunoprecipitation assays from HEK293T cell lysates revealed that CaMKIIα assembles multimeric CaV1.3 LTCC complexes in a Ca2+/calmodulin-dependent manner. CaMKII-dependent assembly of multi-CaV1.3 complexes is further facilitated by co-expression of the CaMKII-binding LTCC β2a subunit, relative to the β3 subunit, which cannot bind directly to CaMKII. Moreover, clustering of surface localized CaV1.3 α1 subunits in intact HEK293 cells was increased by pharmacological LTCC activation, but only in the presence of co-expressed wild-type CaMKIIα. Moreover, depolarization-induced clustering of surface-expressed CaV1.3 LTCCs in cultured hippocampal neurons was disrupted by suppressing the expression of CaMKIIα and CaMKIIβ using shRNAs. The CaMKII-binding RKR motif is conserved in the N-terminal domain of CaV1.2 α1 subunits and we found that activated CaMKIIα promoted the assembly of CaV1.2 homomeric complexes, as well as CaV1.3-CaV1.2 heteromeric complexes in vitro. Furthermore, neuronal depolarization enhanced the clustering of surface-expressed CaV1.2 LTCCs, and enhanced the colocalization of endogenous CaV1.2 LTCCs with surface-expressed CaV1.3, by CaMKII-dependent mechanisms. This work indicates that CaMKII activation-dependent LTCC clustering in the plasma membrane following neuronal depolarization may be essential for the initiation of a specific long-range signal to activate gene expression.

Dataset Information

Memory reconsolidation and its maintenance depend on L-voltage-dependent calcium channels and CaMKII functions regulating protein turnover in the hippocampus.

Publications

Memory reconsolidation and its maintenance depend on L-voltage-dependent calcium channels and CaMKII functions regulating protein turnover in the hippocampus.

Similar Datasets

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