Substrate-selective and Calcium-independent Activation of CaMKII by α-Actinin

Nidhi Jalan-Sakrikar,Ryan K. Bartlett,Anthony J. Baucum,Roger J. Colbran

doi:10.1074/jbc.m112.351817

Nidhi Jalan-Sakrikar, Ryan K. Bartlett + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m112.351817

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Abstract

Protein-protein interactions are thought to modulate the efficiency and specificity of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) signaling in specific subcellular compartments. Here we show that the F-actin-binding protein α-actinin targets CaMKIIα to F-actin in cells by binding to the CaMKII regulatory domain, mimicking CaM. The interaction with α-actinin is blocked by CaMKII autophosphorylation at Thr-306, but not by autophosphorylation at Thr-305, whereas autophosphorylation at either site blocks Ca(2+)/CaM binding. The binding of α-actinin to CaMKII is Ca(2+)-independent and activates the phosphorylation of a subset of substrates in vitro. In intact cells, α-actinin selectively stabilizes CaMKII association with GluN2B-containing glutamate receptors and enhances phosphorylation of Ser-1303 in GluN2B, but inhibits CaMKII phosphorylation of Ser-831 in glutamate receptor GluA1 subunits by competing for activation by Ca(2+)/CaM. These data show that Ca(2+)-independent binding of α-actinin to CaMKII differentially modulates the phosphorylation of physiological targets that play key roles in long-term synaptic plasticity.

Highlights

Synaptic signaling is modulated by protein-protein interactions involving receptor ion channels, cytoskeletal proteins, and protein kinases
Ca2ϩ/CaM stimulated the phosphorylation of all substrates tested, whereas CaMKII activation by the A2-C-terminal domain (CTD) was detected with AC-2 and GluN2B-1290 –1309, but not with syntide-2 (Fig. 1C)
The present findings show that ␣-actinin can function as a novel modulator of CaMKII targeting and kinase activity by mimicking CaM

Summary

Background

Synaptic signaling is modulated by protein-protein interactions involving receptor ion channels, cytoskeletal proteins, and protein kinases. In intact cells, ␣-actinin selectively stabilizes CaMKII association with GluN2B-containing glutamate receptors and enhances phosphorylation of Ser-1303 in GluN2B, but inhibits CaMKII phosphorylation of Ser-831 in glutamate receptor GluA1 subunits by competing for activation by Ca2؉/CaM. These data show that Ca2؉-independent binding of ␣-actinin to CaMKII differentially modulates the phosphorylation of physiological targets that play key roles in long-term synaptic plasticity. In vitro and intact cell studies show that ␣-actinin-2 is a Ca2ϩ-independent, substrate-selective CaMKII activator, which enhances CaMKII interaction with NMDARs containing GluN2B subunits

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION