Dataset Information

CaMKII Phosphorylation of TARP?-8 Is a Mediator of LTP and Learning and Memory.

ABSTRACT: Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated transmission during LTP remains elusive. Here, we identify the hippocampus-enriched TARP?-8, but not TARP?-2/3/4, as a critical CaMKII substrate for LTP. We found that LTP induction increases TARP?-8 phosphorylation, and that CaMKII-dependent enhancement of AMPAR-mediated transmission requires CaMKII phosphorylation sites of TARP?-8. Moreover, LTP and memory formation, but not basal transmission, are significantly impaired in mice lacking CaMKII phosphorylation sites of TARP?-8. Together, these findings demonstrate that TARP?-8 is a crucial mediator of CaMKII-dependent LTP and therefore a molecular target that controls synaptic plasticity and associated cognitive functions.

SUBMITTER: Park J

PROVIDER: S-EPMC5059846 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory.

Park Joongkyu J Chávez Andrés E AE Mineur Yann S YS Morimoto-Tomita Megumi M Lutzu Stefano S Kim Kwang S KS Picciotto Marina R MR Castillo Pablo E PE Tomita Susumu S

Neuron 20160922 1

Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated trans ...[more]

PMID: 27667007

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Project description:Ca(2+)/calmodulin-dependent protein kinase II? (CaMKII?) autophosphorylation at Thr286 and Thr305/Thr306 regulates kinase activity and modulates subcellular targeting and is critical for normal synaptic plasticity and learning and memory. Here, a mass spectrometry-based approach was used to identify Ca(2+)-dependent and -independent in vitro autophosphorylation sites in recombinant CaMKII? and CaMKII?. CaMKII holoenzymes were then immunoprecipitated from subcellular fractions of forebrains isolated from either wild-type (WT) mice or mice with a Thr286 to Ala knock-in mutation of CaMKII? (T286A-KI mice) and analyzed using the same approach in order to characterize in vivo phosphorylation sites in both CaMKII isoforms and identify CaMKII-associated proteins (CaMKAPs). A total of six and seven autophosphorylation sites in CaMKII? and CaMKII?, respectively, were detected in WT mice. Thr286-phosphorylated CaMKII? and Thr287-phosphorylated CaMKII? were selectively enriched in WT Triton-insoluble (synaptic) fractions compared to Triton-soluble (membrane) and cytosolic fractions. In contrast, Thr306-phosphorylated CaMKII? and Ser315- and Thr320/Thr321-phosphorylated CaMKII? were selectively enriched in WT cytosolic fractions. The T286A-KI mutation significantly reduced levels of phosphorylation of CaMKII? at Ser275 across all subcellular fractions and of cytosolic CaMKII? at Ser315 and Thr320/Thr321. Significantly more CaMKAPs coprecipitated with WT CaMKII holoenzymes in the synaptic fraction compared to that in the membrane fraction, with functions including scaffolding, microtubule organization, actin organization, ribosomal function, vesicle trafficking, and others. The T286A-KI mutation altered the interactions of multiple CaMKAPs with CaMKII, including several proteins linked to autism spectrum disorders. These data identify CaMKII isoform phosphorylation sites and a network of synaptic protein interactions that are sensitive to the abrogation of Thr286 autophosphorylation of CaMKII?, likely contributing to the diverse synaptic and behavioral deficits of T286A-KI mice.

Dataset Information

CaMKII Phosphorylation of TARP?-8 Is a Mediator of LTP and Learning and Memory.

Publications

CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory.

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