Protein kinase Mζ

Protein kinase Mζ (also called PKMζ or PKMzeta) is the independent catalytic domain of protein kinase Cζ and, lacking an autoinhibitory regulatory domain of the full-length PKCζ, is constitutively active. This constitutive or autonomous activity allows the kinase to be independent of second messengers and thus persistently active. It was originally thought of as being a cleavage product of full-length PKCζ, an atypical isoform of protein kinase C (PKC). Like other PKC isoforms, PKCζ is a serine/threonine kinase that adds phosphate groups to target proteins. It is atypical in that unlike other PKC isoforms, PKCζ does not require calcium or diacylglycerol (DAG) to become active, but rather relies on a second messenger other than DAG, presumably generated through a phosphoinositide 3-kinase (PI3-kinase) pathway. It is now known that PKMζ is not the result of cleavage of full-length PKCζ, but rather, in mammalian brain, is translated from its own brain-specific mRNA, that is transcribed from the full-length PKCζ gene.cite journal |author=Hernandez AI, Blace N, Crary JF, Serrano PA, Leitges M, Libien JM, Weinstein G, Tcherapanov A, Sacktor TC.
title=Protein kinase M zeta synthesis from a brain mRNA encoding an independent protein kinase C zeta catalytic domain. Implications for the molecular mechanism of memory. |journal=J. Biol. Chem. |volume=278 |issue=41 |pages=40305–16 |year=2003 |url=http://www.jbc.org/cgi/content/full/278/41/40305 |pmid=12857744
doi=10.1074/jbc.M307065200
] The promotor for full-length PKCζ is largely inactive in the forebrain and so PKMζ is the dominant form of ζ in the forebrain and the only PKM that is translated from its own mRNA.

PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation.cite journal |author=Ling D, Benardo L, Serrano P, Blace N, Kelly M, Crary J, Sacktor T |title=Protein kinase Mzeta is necessary and sufficient for LTP maintenance |journal=Nat. Neurosci. |volume=5 |issue=4 |pages=295–6 |year=2002 |url=http://www.nature.com/neuro/journal/v5/n4/full/nn829.html |pmid=11914719 |doi=10.1038/nn829] cite journal |author=Serrano P, Yao Y, Sacktor T |title=Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation |journal=J Neurosci |volume=25 |issue=8 |pages=1979–84 |year=2005 |url=http://0-www.jneurosci.org.library.lausys.georgetown.edu/cgi/content/full/25/8/1979 |pmid=15728837 |doi=10.1523/JNEUROSCI.5132-04.2005] cite journal |author=Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton A, Sacktor T |title=Storage of spatial information by the maintenance mechanism of LTP |journal=Science |volume=313 |issue=5790 |pages=1141–4 |year=2006 |url=http://www.sciencemag.org/cgi/content/full/313/5790/1141 |pmid=16931766 |doi=10.1126/science.1128657] This theory arose from the observation that PKMζ perfused postsynaptically into neurons causes synaptic potentiation and selective inhibitors of PKMζ, when bath applied 1 hr after tetanization, inhibit the late phase or maintenance of LTP. Thus PKMζ is both necessary and sufficient for maintaining LTP. Subsequent work showed that inhibiting the kinase reversed LTP maintenance when applied up to 5 hours after LTP was induced in hippocampal slices, and after 22 hr in vivo. Inhibiting PKMζ in behaving animals erased spatial long-term memories in the hippocampus that were up to 1 month-old, without affecting spatial short-term memories.cite journal |author=Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton A, Sacktor T |title=Storage of spatial information by the maintenance mechanism of LTP |journal=Science |volume=313 |issue=5790 |pages=1141–4 |year=2006 |url=http://www.sciencemag.org/cgi/content/full/313/5790/1141 |pmid=16931766 |doi=10.1126/science.1128657] In the neocortex, thought to be the site of storage for most long-term memories, PKMζ inhibition erased memories for conditioned taste aversion in the insular cortex.cite journal |author=Shema R, Sacktor T, Dudai Y |title=Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMζ|journal=Science |volume=317 |issue=5840 |pages=951–3 |year=2007 |url=http://www.sciencemag.org/cgi/content/full/317/5840/951 |pmid=17702943 |doi=10.1126/science.1144334] PKMζ is thus the first molecule shown to be a component of the storage mechanism of long-term memory.

References

Further reading

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*cite journal | author=Slater SJ, Ho C, Stubbs CD |title=The use of fluorescent phorbol esters in studies of protein kinase C-membrane interactions. |journal=Chem. Phys. Lipids |volume=116 |issue= 1-2 |pages= 75–91 |year= 2003 |pmid= 12093536 |doi=
*cite journal | author=Carter CA, Kane CJ |title=Therapeutic potential of natural compounds that regulate the activity of protein kinase C. |journal=Curr. Med. Chem. |volume=11 |issue= 21 |pages= 2883–902 |year= 2005 |pmid= 15544481 |doi=

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