Protein kinase C zeta type
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| Location (UCSC) | Chr 1: 2.05 – 2.19 Mb | Chr 4: 155.34 – 155.45 Mb | |||||||
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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. 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
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
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]
Alteration in PKMζ may be involved in neurodegeneration Alzheimer's disease.[22]
Inhibitors
- 1,3,5-Trisubstituted Pyrazolines[23]
Interactions
PRKCZ has been shown to interact with:
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000067606 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029053 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8378304.
- ^ PMID 12857744.
- PMID 11836310.
- S2CID 11200668.
- PMID 15728837.
- ^ S2CID 7260010.
- PMID 16672292.
- PMID 19108606.
- PMID 20559553.
- S2CID 15707301.
- PMID 19181618.
- PMID 22348011.
- PMID 23283174.
- PMID 23283171.
- PMID 27187150.
- PMID 27187147.
- PMID 27362229.
- S2CID 17924780.
- PMID 25058929.
- PMID 12162751.
- ^ PMID 10620507.
- PMID 10831594.
- ^ PMID 12893243.
- PMID 9971736.
- PMID 14697253.
- PMID 11158308.
- PMID 12021260.
- S2CID 4427026.
- PMID 15254234.
- ^ PMID 11260256.
- S2CID 15675524.
- PMID 10764742.
- PMID 11781095.
- PMID 9748166.
- PMID 10357815.
- PMID 11684013.
- PMID 10527887.
- PMID 15081397.
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. PMID 12093536.
- 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. PMID 15544481.
