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CaMKII translocation requires local NMDA receptor‐mediated Ca 2+ signaling
Author(s) -
Thalhammer Agnes,
Rudhard York,
Tigaret Cezar M,
Volynski Kirill E,
Rusakov Dmitri A,
Schoepfer Ralf
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601420
Subject(s) - clinical pharmacology , molecular pharmacology , systems pharmacology , library science , pharmacology , medicine , receptor , computer science , drug
Excitatory synaptic transmission and plasticity are critically modulated by N ‐methyl‐ D ‐aspartate receptors (NMDARs). Activation of NMDARs elevates intracellular Ca 2+ affecting several downstream signaling pathways that involve Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII). Importantly, NMDAR activation triggers CaMKII translocation to synaptic sites. NMDAR activation failed to induce Ca 2+ responses in hippocampal neurons lacking the mandatory NMDAR subunit NR1, and no EGFP‐CaMKIIα translocation was observed. In cells solely expressing Ca 2+ ‐impermeable NMDARs containing NR1 N598R ‐mutant subunits, prolonged NMDA application elevated internal Ca 2+ to the same degree as in wild‐type controls, yet failed to translocate CaMKIIα. Brief local NMDA application evoked smaller Ca 2+ transients in dendritic spines of mutant compared to wild‐type cells. CaMKIIα mutants that increase binding to synaptic sites, namely CaMKII‐T286D and CaMKII‐TT305/306VA, rescued the translocation in NR1 N598R cells in a glutamate receptor‐subtype‐specific manner. We conclude that CaMKII translocation requires Ca 2+ entry directly through NMDARs, rather than other Ca 2+ sources activated by NMDARs. Together with the requirement for activated, possibly ligand‐bound, NMDARs as CaMKII binding partners, this suggests that synaptic CaMKII accumulation is an input‐specific signaling event.