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The self-sustained regulation of PKMζ activity during the maintenance of L-LTP
BMC Neuroscience volume 9, Article number: P54 (2008)
What could be the mechanism of enduring synaptic efficacies despite the fast turnover of proteins at synapses? The de-novo synthesis of plasticity related proteins may partially provide the answer. However, the newly synthesized proteins must be activated before they are functional which requires a persistent signal of second messenger. In contrast, to conventional kinases the PKMζ is an autonomous and constitutively active kinase, which does not require a second messenger for its sustained activity. Previous experimental results have shown that inhibiting PKMζ activity can effectively reverse the established L-LTP (3–5 hr in slices and 22 hrs in vivo) [1–3]. Here, we explore a question of what could be the mechanism to regulate the PKMζ activity during the maintenance of L-LTP. We propose a self-sustained regulation of PKMζ activity through another autonomously active kinase PDK1. Here, our specific instantiation of an activity regulation loop is the PKMζ-PDK1 molecular pair. The PDK1 regulates the PKMζ activity and its stability through a phosphorylation cycle . We show that the PKMζ-PDK1 loop acts as a bistable switch. Our results imply that L-LTP induction should produce an increase in the total amount of PKMζ at active synapses, and this increase in PKMζ is maintained through activity regulation in the enduring phase of L-LTP (Fig 1). Our results also show that blocking the PKMζ activity in a dose dependent manner can effectively abolish the increase in total amount of PKMζ, (Fig 2) which is in consistent with previous experimental findings [1, 2].
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Aslam, N., Shouval, H.Z. The self-sustained regulation of PKMζ activity during the maintenance of L-LTP. BMC Neurosci 9, P54 (2008) doi:10.1186/1471-2202-9-S1-P54
- Active Kinase
- Sustained Activity
- Previous Experimental Result
- Synaptic Efficacy
- Fast Turnover