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The self-sustained regulation of PKMζ activity during the maintenance of L-LTP
BMC Neurosciencevolume 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].
Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC: Storage of spatial information by the maintenance mechanism of LTP. Science. 2006, 313: 1141-1144. 10.1126/science.1128657.
Ling DS, Benardo LS, Serrano PA, Blace N, Kelly MT, Crary JF, Sacktor TC: Protein kinase M is necessary and sufficient for LTP maintenance. Nat Neurosci. 2002, 5: 295-296. 10.1038/nn829.
Bliss TV, Collingridge GL, Laroche S: Neuroscience. ZAP and ZIP, a story to forget. Science. 2006, 313: 1058-1059. 10.1126/science.1132538.
Balendran A, Hare GR, Kieloch A, Williams MR, Alessi DR: Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett. 2000, 484: 217-223. 10.1016/S0014-5793(00)02162-1.