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J Neurochem. 2012 Jul;122(2):295-307. doi: 10.1111/j.1471-4159.2012.07787.x. Epub 2012 Jun 6.

Bi-directional regulation of CaMKIIα phosphorylation at Thr286 by NMDA receptors in cultured cortical neurons.

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Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, Michigan, USA.


The N-methyl-D-aspartate (NMDA) receptor (NMDAR)-stimulated autophosphorylation of calmodulin-dependent kinase IIα at Thr286 may regulate many aspects of neuroplasticity. Here, we show that low NMDA concentration (20 μM) up-regulated Thr286 phosphorylation, and high concentration (100 μM) caused dephosphorylation. We next modulated the strength of NMDAR activation by manipulating NMDAR 2A subunit (NR2A) and NMDAR 2B subunit (NR2B), which represent the major NMDAR subtypes in forebrain regions. Pharmacological inhibition and molecular knockdown of NR2A or NR2B blocked 20 μM NMDA-induced phosphorylation. Conversely, over-expression of NR2A or NR2B enhanced phosphorylation by 20 μM NMDA. The 100 μM NMDA-induced dephosphorylation was suppressed by inhibition or knockdown of NR2A or NR2B, and enhanced by over-expression of NR2A or NR2B. Compared to NR2A, NR2B showed a higher impact on the NMDA-stimulated bi-directional regulation of Thr286 phosphorylation. We further found that activation of NR2A and NR2B by 100 μM NMDA-induced dephosphorylation through protein phosphatases (PP) that are inhibited by high concentration okadaic acid (1 μM), but not by PP2A and PP2B inhibitors. This novel function of NMDAR in dynamic regulation of calmodulin-dependent kinase IIα activity provides new evidence to support the current understanding that, depending on the degree of activation, NMDAR may lead to different and even opposing effects on intracellular signaling.

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