Skip to main content

Advertisement

The self-sustained regulation of PKMζ activity during the maintenance of L-LTP

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) [13]. 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 [4]. 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].

Figure 1
figure1

Bistability characteristics of the PKMζ-PDK1 molecular pair.

Figure 2
figure2

Blocking the PKMζ activity during maintenance of L-LTP.

References

  1. 1.

    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.

  2. 2.

    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.

  3. 3.

    Bliss TV, Collingridge GL, Laroche S: Neuroscience. ZAP and ZIP, a story to forget. Science. 2006, 313: 1058-1059. 10.1126/science.1132538.

  4. 4.

    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.

Download references

Author information

Correspondence to Naveed Aslam.

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Keywords

  • Active Kinase
  • Sustained Activity
  • Previous Experimental Result
  • Synaptic Efficacy
  • Fast Turnover