Protein kinase C, zeta (PKCζ) also known as PRKCZ is an enzyme that in humans 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. The truncated PKMζ is thought to be responsible for maintaining long-term memories in the brain.
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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 autoinhibition of the PKC catalytic 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.[1]
PKMζ is the independent catalytic domain of protein kinase Cζ (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.[1] 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.
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.[2]
PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP).[3][4][5] This theory arose from the observation that PKMζ perfused post synaptically into neurons causes synaptic potentiation, and selective inhibitors of PKMζ, when bath applied one hour 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 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[5], and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.[6] 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.[7][8] PKMζ is thus the first molecule shown to be a component of the storage mechanism of long-term memory.
Recent research has demonstrated alteration in PKMζ in Alzheimer's disease (see Long-term potentiation), providing a potential link between this kinase and neurodegeneration.[9]
PRKCZ has been shown to interact with CENTA1,[10] PDPK1,[11][12][13][14] PARD6A,[15][16][17] Src,[18] NFATC2,[19] PAWR,[20] YWHAQ,[21] WWC1,[22] C-Raf,[21] AKT3,[23] PARD6B,[17] RELA,[24] FEZ1,[25] YWHAB,[21] FEZ2,[26] C1QBP,[27] YWHAZ[10][21] and MAP2K5.[28]
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