Protein kinase C zeta type explained

Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein in humans that is encoded by the PRKCZ gene. The PRKCZ gene encodes at least two alternative transcripts, the full-length PKCζ and an N-terminal truncated form PKMζ. PKMζ is thought to be responsible for maintaining long-term memories in the brain.[1] The importance of PKCζ in the creation and maintenance of long-term potentiation was first described by Todd Sacktor and his colleagues at the SUNY Downstate Medical Center in 1993.[2]

Structure

PKC-zeta has an N-terminal regulatory domain, followed by a hinge region and a C-terminal catalytic domain. Second messengers stimulate PKCs by binding to the regulatory domain, translocating the enzyme from cytosol to membrane, and producing a conformational change that removes auto-inhibition of the PKC catalytic protein kinase activity. PKM-zeta, a brain-specific isoform of PKC-zeta generated from an alternative transcript, lacks the regulatory region of full-length PKC-zeta and is therefore constitutively active.[3]

PKMζ is the independent catalytic domain of PKCζ and, lacking an autoinhibitory regulatory domain of the full-length PKCζ, is constitutively and persistently active, without the need of a second messenger. 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 different second messenger, 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 the mammalian brain, is translated from its own brain-specific mRNA, that is transcribed by an internal promoter within the PKCζ gene.[3] The promoter 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.

Function

PKCζ

Atypical PKC (aPKC) isoforms [zeta (this enzyme) and [[PRKCI|lambda/iota]]] play important roles in insulin-stimulated glucose transport. Human adipocytes contain PKC-zeta, rather than PKC-lambda/iota, as their major aPKC. Inhibition of the PKCζ enzyme inhibits insulin-stimulated glucose transport while activation of PKCζ increases glucose transport.[4]

PKMζ

PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP).[5] [6] [7] LTP is one of the major cellular mechanisms that are widely considered to underlie learning and memory.[8] This theory arose from the observation that PKMζ perfused into neurons causes synaptic potentiation, and selective inhibitors of PKMζ like zeta inhibitory peptide (ZIP), when bath applied one hour after tetanization, inhibit the late phase or maintenance of LTP. Thus, PKMζ was thought to be both necessary and sufficient for maintaining LTP. Subsequent work showed that inhibiting PKMζ reversed LTP maintenance when applied up to 5 hours after LTP was induced in hippocampal slices, and after 22 hours in vivo. Inhibiting PKMζ in behaving animals erased spatial long-term memories in the hippocampus that were up to one month old, without affecting spatial short-term memories,[7] and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.[9] When ZIP was injected into rats' sensorimotor cortices, it erased muscle memories for a task, even after several weeks of training.[10] PKMζ may form a self-perpetuating, positive feedback loop that can persist for months to maintain very long-term memories.

In the neocortex, thought to be the site of storage for most long-term memories, PKMζ inhibition erased associative memories for conditioned taste aversion in the insular cortex, up to 3 months after training.[11] [12] The protein also seems to be involved, through the nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction.[13] Although results from PKCζ/PKMζ-null mice demonstrate LTP and memory appear largely the same as wild-type mice,[14] [15] the normal function of PKMζ in LTP and long-term memory storage was shown to be compensated by the other atypical PKC isoform, PKCι/λ in the knock-out.[16] [17] [18]

Alteration in PKMζ may be involved in neurodegeneration Alzheimer's disease.[19]

Inhibitors

Interactions

PRKCZ has been shown to interact with:

Further reading

Notes and References

  1. Sacktor, TC . Memory maintenance by PKMζ--an evolutionary perspective. . 5 . 31 . 2012 . 10.1186/1756-6606-5-31 . free. 3517905 . 22986281 .
  2. Sacktor TC, Osten P, Valsamis H, Jiang X, Naik MU, Sublette E . Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation . Proceedings of the National Academy of Sciences of the United States of America . 90 . 18 . 8342–8346 . 1993 . 8378304 . 47352 . 10.1073/pnas.90.18.8342 . 1993PNAS...90.8342S . free .
  3. Hernandez AI, Blace N, Crary JF, Serrano PA, Leitges M, Libien JM, Weinstein G, Tcherapanov A, Sacktor TC . 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 . J. Biol. Chem. . 278 . 41 . 40305–16 . October 2003 . 12857744 . 10.1074/jbc.M307065200 . free .
  4. Bandyopadhyay G, Sajan MP, Kanoh Y, Standaert ML, Quon MJ, Lea-Currie R, Sen A, Farese RV . PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human adipocytes . J. Clin. Endocrinol. Metab. . 87 . 2 . 716–23 . February 2002 . 10.1210/jcem.87.2.8252 . 11836310 . free .
  5. Ling DS, Benardo LS, Serrano PA, Blace N, Kelly MT, Crary JF, Sacktor TC . Protein kinase Mzeta is necessary and sufficient for LTP maintenance . Nat. Neurosci. . 5 . 4 . 295–6 . 2002 . 11914719 . 10.1038/nn829 . 11200668 .
  6. Serrano P, Yao Y, Sacktor TC . Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation . J Neurosci . 25 . 8 . 1979–84 . 2005 . 15728837 . 10.1523/JNEUROSCI.5132-04.2005 . 6726070 . free .
  7. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC . Storage of spatial information by the maintenance mechanism of LTP . Science . 313 . 5790 . 1141–4 . 2006 . 16931766 . 10.1126/science.1128657 . 2006Sci...313.1141P . 10.1.1.453.2136 . 7260010 .
  8. Cooke SF, Bliss TV . Plasticity in the human central nervous system . Brain . 129 . Pt 7 . 1659–73 . 2006 . 16672292 . 10.1093/brain/awl082 . free .
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