Application of ZIP to block the constitutive activity of PKMζ



Long-term potentiation (LTP) is a persistent synaptic enhancement which is thought to be a substrate for memory. It has been proved that the constitutively active form of an atypical protein kinase C (PKC) isozyme, protein kinase M zeta (PKMζ), is sufficient and necessary and for LTP maintenance. The myristoylated z-pseudosubstrate inhibitory peptide (ZIP) as a cell-permeable, selective peptide inhibitor of PKMζ, can block the constitutive activity of PKMζ.

Pharmacologic action

By reconstituting the autoinhibition of the absent PKCζ regulatory domain, ZIP can inhibit PKMζ potently and selectively. Consisting of the ζ pseudosubstrate sequence with a myristoyl moiety (wavy line) allowing for cell permeability, ZIP can block the constitutive activity of PKMζ by reconstituting the inhibition of the missing regulatory domain. Establishing potentiation at synapses may require more PKMζ–substrate interactions than maintaining potentiation because ZIP is a competitive inhibitor of protein substrate binding to PKMζ.


Bathing ZIP to hippocampal slices reverses established late LTP and inhibits the synaptic potentiation produced by intracellular perfusion of PKMζ, without affecting baseline or reversing early LTP, and nontetanized synaptic transmission. By postsynaptic perfusion of PKMζ through a whole-cell recording pipette bath application of myristoylated ZIP blocked potentiation of AMPAR EPSCs produced. The whole-cell recordings indicated potentiation of evoked AMPAR responses by PKMζ (open squares; p < 0.05 for values between 1 and 12 min of recording). Bath application of 1 μM showed partial inhibition (filled triangles) and 5 μM ZIP showed strong inhibition of potentiation (filled circles). Control baseline recordings without PKMζ in the pipette or inhibitor are shown (open circles); n = 4 for all of the experiments. Besides, application of ZIP had no influence on baseline or early LTP (5 μM; n = 5) but prevented the late phase, with the potentiated pathway returning to baseline in 3 h. There was a significant reduction of the initial potentiation by 2 h after tetanization (p < 0.05) while no effect was observed on the nontetanized pathway.

Pharmacokinetics and metabolism

22 hours after the last training session, both hippocampi was not injected either saline or ZIP. 2 hours later, long-term retention was tested on the device without shock (i.e., extinction testing). The saline-injected animals proved long-term spatial information storage by avoiding initial entry into the shock zone and spending less time in the shock zone. On the contrary, the animals injected ZIP failed to prove spatial information storage by not avoiding entry into the shock zone, actively exploring the whole device and by spending time in the shock zone which is close to the level of chance.


1. D. S. Ling, L. S. Benardo, P. A. Serrano, N. Blace, M. T. Kelly, J. F. Crary and T. C. Sacktor. Protein kinase Mζ is necessary and sufficient for LTP maintenance. Nature Neurosci., 2002, 5(4), 295.

2. C. Laudanna, D. Mochly-Rosen, T. Liron, G. Constantin and E. C. Butcher. Evidence of ζ protein kinase C involvement in polymorphonuclear neutrophil integrin-dependent adhesion and chemotaxis. J. Biol. Chem., 1998, 273(46), 30306-30315.

3. E. Pastalkova, P. Serrano, D. Pinkhasova, E. Wallace, A. A. Fenton and T. C. Sacktor. Storage of spatial information by the maintenance mechanism of LTP. Science, 2006, 313(5790), 1141-1144.

4. P. Serrano, Y. Yao and T. C. Sacktor. Persistent phosphorylation by protein kinase Mζ maintains late-phase long-term potentiation. J. Neurosci., 2005, 25(8), 1979-1984.

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