Involvement of γ protein kinase C in estrogen‐induced neuroprotection against focal brain ischemia through G protein‐coupled estrogen receptor

Hayashi, Shigeto; Ueyama, Takeshi; Kajimoto, Tetsuya; Yagi, Kazuichi; Kohmura, Eiji; Saito, Naoaki

doi:10.1111/j.1471-4159.2005.03080.x

Cited by 37 publications

(25 citation statements)

References 34 publications

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“…Injection of estrogen (i.p.) after the start of reperfusion can significantly reduce the infarct volume in males but such a protective effect was attenuated in PKCγ-knockout mice [160]. These data suggest neuroprotective values of estrogen against cerebral ischemia, although in humans, clinical evidence for stroke prevention with hormone replacement therapy remains inconclusive.…”

Section: Ischemic Dementiamentioning

confidence: 96%

“…Female animals are less vulnerable to ischemiainduced neuronal damage [156,157] and estrogen treatment protects the brain from experimental stroke [158,159]. Transient unilateral middle cerebral artery occlusion (90 min) followed by 22.5 h reperfusion has been shown to produce smaller total infarct size in C57BL/6 female mice than in the male mice, but such difference was not observed in PKCγ knock-out mice [160]. Injection of estrogen (i.p.)…”

Section: Ischemic Dementiamentioning

confidence: 98%

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Protein Kinase C Pharmacology: Perspectives on Therapeutic Potentials as Antidementic and Cognitive Agents

Sun

Alkon²

2006

RPCN

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Activity of protein kinase C (PKC) isozymes plays a critical role in various types of learning and memory. In addition, abnormal functions of PKC signal cascades in neurons represent one of the earliest changes in the brains of patients with Alzheimer's disease (AD) and dementia related to ischemic/stroke events. In preclinical studies, inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of PKC isozymes has been found to enhance learning and memory and/or to produce antidementic effects. The PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity but also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation in the brain. These observations strongly suggest that PKC pharmacology may represent an attractive area for the development of cognitive therapeutics and agents against dementia in the future.

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Section: Ischemic Dementiamentioning

confidence: 96%

Section: Ischemic Dementiamentioning

confidence: 98%

Protein Kinase C Pharmacology: Perspectives on Therapeutic Potentials as Antidementic and Cognitive Agents

Sun

Alkon²

2006

RPCN

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“…In this animal model, spatial memory was mildly affected and long-term synaptic potentiation in hippocampus was impaired; 22 these animals also present a reduced neuroprotection by estrogens after ischemia. 23 In the PKCα null mice long-term synaptic depression is not inducible in the cerebellum 24 while mice lacking PKCβ suffer from a deficit in both cued and contextual fear conditioning. 25 The PKCε null mice indicate an involvement of this isoform in pain states and in the action of sedative drugs and in alcohol consumption.…”

Section: Pkc Isoform-specific Brain Functionsmentioning

confidence: 99%

“…Calcium dependent PKC activity (A) and translocation (B) was assayed utilizing histone as substrate as described. 38 Calcium-independent PKC activity (C) and translocation (D) was assayed utilizing (Ser 25 ) PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] as substrate as described. 41 Translocation is reported as ratio of activity in membranes and soluble fractions after treatment with PMA 160 nM for 15 min.…”

Section: Kinase Activity Shows Strain and Substrate-dependent Changesmentioning

confidence: 99%

Protein Kinase C Signal Transduction Regulation in Physiological and Pathological Aging

Battaini

2005

Annals of the New York Academy of Sciences

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Calcium/phospholipid-regulated protein kinase C (PKC) signalling is known to be involved in cellular functions relevant to brain health and disease, including ion channel modulation, receptor regulation, neurotransmitter release, synaptic plasticity, and survival. Brain aging is characterized by altered neuronal molecular cascades and interneuronal communication in response to various stimuli. In the last few years we have provided evidence that in rodents, despite no changes in PKC isoform levels (both calcium dependent and calcium independent), the activation/translocation process of the calcium-dependent and -independent kinases and the content of the adaptor protein RACK1 (receptor for activated C kinase-1) are deficient in physiological brain aging. Moreover, human studies have shown that PKC and its adaptor protein RACK1 are also interdependent in pathological brain aging (e.g., Alzheimer's disease); in fact, calcium-dependent PKC translocation and RACK1 levels are both deficient in an area-selective manner. These data point to the notion that, in addition to a well-described lipid environment alteration, changes in protein-protein interactions may impair the mechanisms of PKC activation in aging. It is interesting to note that interventions to counteract the age-related functional loss also restore PKC activation and the adaptor protein machinery expression. A better insight into the factors controlling PKC activation may be important not only to elucidate the molecular basis of signal transmission, but also to identify new strategies to correct or even to prevent agedependent alterations in cell-to-cell communication.

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“…For example, the conventional isoform, PKCγ, is activated directly by hydrogen peroxide (Lin, et al, 2005). PKCγ is most noted for its function in neural tissue and likely acts in a neural protective role (Hayashi, 2005). Other PKCs, including PKCε, are activated by hypoxia, through unknown mechanisms (Cai, 2003).…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C epsilon activates lens mitochondrial cytochrome c oxidase subunit IV during hypoxia

Barnett

Lin

Akoyev

et al. 2008

Experimental Eye Research

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Protein Kinase C (PKC) isoforms have been identified as major cellular signaling proteins that act directly in response to oxidation conditions. In retina and lens two isoforms of PKC respond to changes in oxidative stress, PKCγ and PKCε, while only PKCε is found in heart. In heart the PKCε acts on connexin 43 to protect from hypoxia. The presence of both isoforms in the lens led to this study to determine if lens PKCε had unique targets. Both lens epithelial cells in culture and whole mouse lens were examined using PKC isoform-specific enzyme activity assays, coimmunoprecipitation, confocal microscopy, immunoblots, and light and electron microscopy. PKCε was found in lens epithelium and cortex but not in the nucleus of mouse lens. The PKCε isoform was activated in both epithelium and whole lens by 5% oxygen when compared to activity at 21% oxygen. In hypoxic conditions (5% oxygen) the PKCε co-immunoprecipitated with the mitochondrial cytochrome C oxidase IV subunit (CytCOx). Concomitant with this the CytCOx enzyme activity was elevated and increased co-localization of CytCOx with PCKε was observed using immunolabeling and confocal microscopy. In contrast, no hypoxia-induced activation of CytCOx was observed in lenses from the PKCε knockout mice. Lens from 6 week old PKCε knockout mice had a disorganized bow region which was filled with vacuoles indicating a possible loss of mitochondria but the size of the lens was not altered. Electron microscopy demonstrated that the nuclei of the PCKε knockout mice were abnormal in shape. Thus, PKCε is found to be activated by hypoxia and this results in the activation of the mitochondrial protein CytCOx. This could protect the lens from mitochondrial damage under the naturally hypoxic conditions observed in this tissue. Lens oxygen levels must remain low. Elevation of oxygen which occurs during vitreal detachment or liquification is associated with cataracts. We hypothesize that elevated oxygen could cause inhibition of PKCε resulting in a loss of mitochondrial protection.

show abstract

Involvement of γ protein kinase C in estrogen‐induced neuroprotection against focal brain ischemia through G protein‐coupled estrogen receptor

Cited by 37 publications

References 34 publications

Protein Kinase C Pharmacology: Perspectives on Therapeutic Potentials as Antidementic and Cognitive Agents

Protein Kinase C Pharmacology: Perspectives on Therapeutic Potentials as Antidementic and Cognitive Agents

Protein Kinase C Signal Transduction Regulation in Physiological and Pathological Aging

Protein kinase C epsilon activates lens mitochondrial cytochrome c oxidase subunit IV during hypoxia

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