Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein in humans that is encoded by the PRKCZgene. 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. 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.[5]
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.[6]
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.[6] 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
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.[7]
PKMζ
PKMζ is thought to be responsible for maintaining the late phase of
long-term potentiation (LTP).[8][9][10] LTP is one of the major cellular mechanisms that are widely considered to underlie
learning and
memory.[11] 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,[10] and erased long-term memories for fear conditioning and inhibitory avoidance in the
basolateral amygdala.[12] When ZIP was injected into rats'
sensorimotor cortices, it erased
muscle memories for a task, even after several weeks of training.[13] 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.[14][15] The protein also seems to be involved, through the
nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction.[16] Although results from PKCζ/PKMζ-null mice demonstrate LTP and memory appear largely the same as wild-type mice,[17][18] 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.[19][20][21]
^Hodgkinson CP, Sale EM, Sale GJ (2002). "Characterization of PDK2 activity against protein kinase B gamma". Biochemistry. 41 (32): 10351–9.
doi:
10.1021/bi026065r.
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^
abZemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, Johannes FJ, Aitken A (2003). "Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C". Biochem. Biophys. Res. Commun. 307 (3): 459–65.
doi:
10.1016/S0006-291X(03)01187-2.
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^Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005). "Towards a proteome-scale map of the human protein–protein interaction network". Nature. 437 (7062): 1173–8.
Bibcode:
2005Natur.437.1173R.
doi:
10.1038/nature04209.
PMID16189514.
S2CID4427026.
^Hodgkinson CP, Sale GJ (2002). "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry. 41 (2): 561–9.
doi:
10.1021/bi010719z.
PMID11781095.
^Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ (1998). "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science. 281 (5385): 2042–5.
Bibcode:
1998Sci...281.2042A.
doi:
10.1126/science.281.5385.2042.
PMID9748166.
^Seibenhener ML, Roehm J, White WO, Neidigh KB, Vandenplas ML, Wooten MW (1999). "Identification of Src as a novel atypical protein kinase C-interacting protein". Mol. Cell Biol. Res. Commun. 2 (1): 28–31.
doi:
10.1006/mcbr.1999.0140.
PMID10527887.
^Büther K, Plaas C, Barnekow A, Kremerskothen J (2004). "KIBRA is a novel substrate for protein kinase Czeta". Biochem. Biophys. Res. Commun. 317 (3): 703–7.
doi:
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PMID15081397.
Further reading
Slater SJ, Ho C, Stubbs CD (2003). "The use of fluorescent phorbol esters in studies of protein kinase C-membrane interactions". Chem. Phys. Lipids. 116 (1–2): 75–91.
doi:
10.1016/S0009-3084(02)00021-X.
PMID12093536.
Carter CA, Kane CJ (2005). "Therapeutic potential of natural compounds that regulate the activity of protein kinase C". Curr. Med. Chem. 11 (21): 2883–902.
doi:
10.2174/0929867043364090.
PMID15544481.