Selective translocation of Ca2+/calmodulin protein kinase IIalpha (CaMKIIalpha) to inhibitory synapses.
Ca(2+)/calmodulin protein kinase IIα (CaMKIIα) has a central role in regulating neuronal excitability. It is well established that CaMKIIα translocates to excitatory synapses following strong glutamatergic stimuli that induce NMDA-receptor (NMDAR)-dependent long-term potentiation in CA1 hippocampal neurons. We now show that CaMKIIα translocates to inhibitory but not excitatory synapses in response to more moderate NMDAR-activating stimuli that trigger GABA(A)-receptor (GABA(A)R) insertion and enhance inhibitory transmission. Such moderate NMDAR activation causes Thr286 autophosphorylation of CaMKIIα, which our results demonstrate is necessary and sufficient, under basal conditions, to localize CaMKIIα at inhibitory synapses and enhance surface GABA(A)R expression. Although stronger glutamatergic stimulation coupled to AMPA receptor insertion also elicits Thr286 autophosphorylation, accumulation of CaMKIIα at inhibitory synapses is prevented under these conditions by the phosphatase calcineurin. This preferential targeting of CaMKIIα to glutamatergic or GABAergic synapses provides neurons with a mechanism whereby activity can selectively potentiate excitation or inhibition through a single kinase mediator.
Dominick P. Purpura Department of Neuroscience, The Rose Kennedy Center for Mental Retardation, The Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA.
Kurt C
KC
Marsden
Adi
A
Shemesh
K Ulrich
KU
Bayer
Reed C
RC
Carroll
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000502:physiology*; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin