Conventional protein kinase C in the brain: 40 years later

Callender, Julia A.; Newton, Alexandra C.

doi:10.1042/ns20160005

Cited by 73 publications

(63 citation statements)

References 115 publications

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“…PKC consists of a gene family divided into three classes: conventional PKCs α, β, and γ; novel PKCs δ, ε, η, and θ; and atypical PKCζ and PKCι/λ (human PKCι and rodent PKCλ are orthologous genes) (11, 12). Most PKCs consist of a regulatory domain and a catalytic domain.…”

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confidence: 99%

The genetics of PKMζ and memory maintenance

Sacktor

Hell

2017

Sci. Signal.

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Elucidating the molecular mechanisms that maintain long-term memory is a fundamental goal of neuroscience. Accumulating evidence suggests that persistent signaling by the atypical protein kinase C (PKC) isoform protein kinase Mζ (PKMζ) might maintain synaptic long-term potentiation (LTP) and long-term memory. However, the role of PKMζ has been challenged by genetic data from PKMζ-knockout mice showing intact LTP and long-term memory. Moreover, the PKMζ inhibitor peptide ζ inhibitory peptide (ZIP) reverses LTP and erases memory in both wild-type and knockout mice. Data from four papers using additional isoform-specific genetic approaches have helped to reconcile these conflicting findings. First, a PKMζ-antisense approach showed that LTP and longterm memory in PKMζ-knockout mice are mediated through a compensatory mechanism that depends on another ZIP-sensitive atypical isoform, PKCι/λ. Second, short hairpin RNAs decreasing the amounts of individual atypical isoforms without inducing compensation disrupted memory in different temporal phases. PKCι/λ knockdown disrupted short-term memory, whereas PKMζ knockdown specifically erased long-term memory. Third, conditional PKCι/λ knockout induced compensation by rapidly activating PKMζ to preserve short-term memory. Fourth, a dominant-negative approach in the model system Aplysia revealed that multiple PKCs form PKMs to sustain different types of long-term synaptic facilitation, with atypical PKM maintaining synaptic plasticity similar to LTP. Thus, under physiological conditions, PKMζ is the principal PKC isoform that maintains LTP and long-term memory. PKCι/λ can compensate for PKMζ, and because other isoforms could also maintain synaptic facilitation, there may be a hierarchy of compensatory mechanisms maintaining memory if PKMζ malfunctions.

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confidence: 99%

The genetics of PKMζ and memory maintenance

Sacktor

Hell

2017

Sci. Signal.

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“…It has been documented that following insulin binding to the receptor, in addition to Akt activation, some isoforms of PKC such as PKC ζ and PKMζ can be activated. The activation of these PKC isoforms, called atypical PKC and highly expressed in the brain, results in GSK3β phosphorylation on Ser9 residue and inactivates it . The effect of MA administration on atypical PKC function is less studied, but few studies indicated that MA administration caused PKMζ inactivation in hippocampus, which is associated with memory impairments, whereas in striatum it activates PKC ζ and PKMζ followed by increases in tyrosine hydroxylase and DAT .…”

Section: Discussionmentioning

confidence: 99%

Increasing methamphetamine doses inhibit glycogen synthase kinase 3β activity by stimulating the insulin signaling pathway in substantia nigra

Valian

Ahmadiani

Dargahi

2018

J of Cellular Biochemistry

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Methamphetamine (MA), a highly abused psychostimulant, exerts neurotoxic effects on the dopaminergic system via several neurotoxicity mechanisms in the long-term administration. Since the effect of MA on the signaling insulin pathway is less studied, the current study was designed to evaluate the effect of escalating an MA regimen on different insulin signaling elements in substantia nigra (SN) and striatum of a rat. Increasing MA doses (1-14 mg/kg) were administrated intraperitoneally twice a day for 14 days in rats. In the control group, normal saline was injected in the same volume. On days 1, 14, 28, and 60 after MA discontinuation, molecular assessments were performed. Insulin receptor (IR) and insulin receptor substrate (IRS) 1 and 2 gene expression were evaluated using real-time polymerase chain reaction, and protein levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phospho-PI3K, Akt, phospho-Akt, glycogen synthase kinase 3β (GSK3β), and phospho-GSK3β were measured by the Western blot analysis in SN and striatum. Messenger RNA levels of IR and insulin receptor substrate 2 were increased in SN, 1 day after the last injection. Although no changes were observed in PI3K, phospho-PI3K, Akt, phospho-Akt, and GSK3β levels, increase in the level of inactive form of GSK3β (phosphorylated on serine 9) was indicated in SN on day 28. In striatum, decreases in IR and phospho-Akt were demonstrated, without any change in other elements. Repeated escalating regimen of MA activated the insulin signaling pathway and inhibited GSK3β activity in SN. This response, which did not occur in striatum, may act as an adaptive mechanism to prevent MA-induced neurotoxicity in dopaminergic cell bodies.

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“…PKC enzymes are regulated at the level of structure, function and subcellular localization [1][2][3][4][5][6][7][8][9]. PKC enzyme dysfunction has been linked to many human disease pathologies, including cancer, diabetes and heart disease [10][11][12][13][14][15][16][17]. PKC modulates aspects of cellular physiology, such as angiogenesis, cellular motility, proliferation, differentiation and apoptosis [18].…”

Section: Introductionmentioning

confidence: 99%

“…Differential expression and activity of PKC has been linked to most types of cancer, including carcinomas (e.g., breast, colorectal), sarcomas (e.g., glioma), lymphomas (e.g., diffuse large Bcell lymphoma) and leukemias [10][11][12][13][14][15]. Generally, loss of PKC function has been linked to cancer, whereas enhanced activity has been linked to neurodegeneration [16]. Many groundbreaking investigations during the last two decades have suggested that PKC enzymes have novel therapeutic potential as drug targets in different cancers, heart failure and neurodegenerative diseases [10][11][12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Generally, loss of PKC function has been linked to cancer, whereas enhanced activity has been linked to neurodegeneration [16]. Many groundbreaking investigations during the last two decades have suggested that PKC enzymes have novel therapeutic potential as drug targets in different cancers, heart failure and neurodegenerative diseases [10][11][12][13][14][15][16][17][18][19]. Diverse catalytic and regulatory mechanisms exist within the PKC enzyme family, providing a plethora of possibilities for drug target design [18][19][20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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A systems biology-based molecular model of the protein kinase C life cycle

Aslam

Alvi

2019

Preprint

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Protein kinase C (PKC) enzymes are a family of kinases that mediate signal transduction originating at the cell surface. Most cell membranes can contain functional PKC enzymes. Aberrations in the PKC life cycle may result cellular damage and dysfunction. For example, some cancerous cells exhibit alterations in PKC activity. Here, we use a systems biology approach to describe a molecular model of the PKC life cycle. Understanding the PKC life cycle is necessary to identify new anticancer drug targets. The PKC life cycle is composed of three key regulatory processes: maturation, activation and termination. These processes precisely control PKC enzyme levels. This model describes the fate of PKC during de novo synthesis and PKC's lipid-mediated activation cycle. We utilize a systems biology approach to show the PKC life cycle is controlled by multiple phosphorylation and dephosphorylation events. PKC processing events can be divided into two types: maturation via processing of newly synthesized enzyme and secondary messenger-dependent activation of dormant, but catalyticallycompetent enzyme. Newly synthesized PKC enzyme is constitutively processed through three ordered phosphorylations and stored in the cytosol as a stable, signaling-competent inactive and autoinhibited molecule. Upon extracellular stimulation, diacylglycerol (DAG) and calcium ion (Ca +2 ) generated at the membrane bind PKC. PKC then undergoes cytosol-to-membrane translocation and subsequent activation. Our model shows that, once activated, PKC is prone to dephosphorylation and subsequent degradation. This model also describes the role of HSP70 in stabilization and re-phosphorylation of dephosphorylated PKC, replenishing the PKC pool. Our model shows how the PKC pool responds to different intensities of extracellular stimuli? We show that blocking PHLPP dephosphorylation replenishes the PKC pool in a dose-dependent manner. This model provides a comprehensive understanding of PKC life cycle regulation.

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Conventional protein kinase C in the brain: 40 years later

Cited by 73 publications

References 115 publications

The genetics of PKMζ and memory maintenance

The genetics of PKMζ and memory maintenance

Increasing methamphetamine doses inhibit glycogen synthase kinase 3β activity by stimulating the insulin signaling pathway in substantia nigra

A systems biology-based molecular model of the protein kinase C life cycle

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