A structural mechanism for maintaining the 'on-state' of the CaMKII memory switch in the post-synaptic density.
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated by Ca(2+) entry into neurons. Autophosphorylation of T286 is of special importance because it makes the enzyme active in the absence of Ca(2+), providing a biochemical memory that is critical for plasticity. To understand the factors controlling the duration of this state of CaMKII, we studied dephosphorylation of CaMKII in the post-synaptic density (PSD), a structure that defines a neuronal subcompartment critical for plasticity. We found that PSD-resident PP1 can dephosphorylate many sites on CaMKII, but not the T286 site that produces Ca(2+)-independent activity. This, together with previous work showing that soluble PP2A cannot dephosphorylate PSD CaMKII, provides a novel explanation for the in vivo persistence of T286 phosphorylation: after activated CaMKII translocates from the cytoplasm to the PSD, structural constraints prevent phosphatases from dephosphorylating T286. These results also suggest that the PSD is more than a simple scaffold for synaptic proteins; it may act to regulate the activity of proteins by positioning them in orientations that either prevent or favor specific biochemical reactions.
Mullasseril
Praseeda
P
Department of Biology, Brandeis University, Waltham, Massachusetts, USA.
Dosemeci
Ayse
A
Lisman
John E
JE
Griffith
Leslie C
LC
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002540:Cerebral Cortex / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D008568:Memory / Q000502:physiology*; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000737:chemistry / Q000378:metabolism*
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases