Protein kinase C zeta type

Protein kinase C, zeta (PKCζ), also known as PRKCZ, is an is_associated_with::enzyme that in humans is encoded by the PRKCZ is_associated_with::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. The importance of PKCζ in the creation and maintenance of is_associated_with::long-term potentiation was first described by Todd Sacktor and his colleagues at the State University of New York at Brooklyn in 1993.

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

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 is_associated_with::protein kinase C (PKC). Like other PKC isoforms, PKCζ is a is_associated_with::serine/threonine kinase that adds is_associated_with::phosphate groups to target is_associated_with::proteins. It is atypical in that unlike other PKC isoforms, PKCζ does not require is_associated_with::calcium or diacylglycerol (DAG) to become active, but rather relies on a different second messenger, presumably generated through a is_associated_with::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 is_associated_with::mRNA, that is transcribed by an internal promoter within the PKCζ gene. The promoter for full-length PKCζ is largely inactive in the is_associated_with::forebrain and so PKMζ is the dominant form of ζ in the forebrain and the only PKM that is translated from its own mRNA.

PKCζ
Atypical PKC (aPKC) isoforms [zeta (this enzyme) and lambda/iota] play important roles in is_associated_with::insulin-stimulated glucose transport. Human is_associated_with::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.

PKMζ
PKMζ is thought to be responsible for maintaining the late phase of is_associated_with::long-term potentiation (LTP);   However, transgenic mice lacking PKMζ demonstrate normal LTP. LTP is one of the major cellular mechanisms that are widely considered to underlie is_associated_with::learning and is_associated_with::memory. This theory arose from the observation that PKMζ perfused post synaptically into is_associated_with::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 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 is_associated_with::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, and erased long-term memories for fear conditioning and inhibitory avoidance in the is_associated_with::basolateral amygdala. When ZIP was injected into rats' sensorimotor cortices, it erased muscle memories for a task, even after several weeks of training. In the is_associated_with::neocortex, thought to be the site of storage for most long-term memories, PKMζ inhibition erased associative memories for conditioned taste aversion in the is_associated_with::insular cortex, up to 3 months after training. The protein also seems to be involved, through the is_associated_with::nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction. PKMζ is thus the first molecule shown to be a component of the storage mechanism of is_associated_with::long-term memory, however this function has recently been challenged.

Recent research has demonstrated alteration in PKMζ in is_associated_with::Alzheimer's disease (see Long-term potentiation), providing a potential link between this kinase and neurodegeneration.

Model organisms
is_associated_with::Model organisms have been used in the study of PRKCZ function. A conditional is_associated_with::knockout mouse line, called Prkcztm1a(EUCOMM)Wtsi was generated as part of the is_associated_with::International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.

Male and female animals underwent a standardized is_associated_with::phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on is_associated_with::mutant mice and three significant abnormalities were observed. Homozygous mutant males had is_associated_with::Bergmeister's papilla, while both sexes had atypical plasma chemistry and abnormal is_associated_with::melanocyte morphology.

Inhibitors

 * 1,3,5-Trisubstituted Pyrazolines

Interactions
PRKCZ has been shown to interact with:


 * is_associated_with::AKT3,
 * is_associated_with::C-Raf,
 * is_associated_with::C1QBP,
 * CENTA1,
 * is_associated_with::FEZ1,
 * is_associated_with::FEZ2,
 * is_associated_with::MAP2K5,
 * is_associated_with::NFATC2,
 * is_associated_with::PARD6A,
 * is_associated_with::PARD6B,
 * is_associated_with::PAWR,
 * PDPK1,
 * is_associated_with::RELA,
 * Src,
 * is_associated_with::WWC1,
 * is_associated_with::YWHAB, and
 * is_associated_with::YWHAQ,
 * is_associated_with::YWHAZ.