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      Conventional protein kinase C in the brain: 40 years later

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          Abstract

          Protein kinase C (PKC) is a family of enzymes whose members transduce a large variety of cellular signals instigated by the receptor-mediated hydrolysis of membrane phospholipids. While PKC has been widely implicated in the pathology of diseases affecting all areas of physiology including cancer, diabetes, and heart disease—it was discovered, and initially characterized, in the brain. PKC plays a key role in controlling the balance between cell survival and cell death. Its loss of function is generally associated with cancer, whereas its enhanced activity is associated with neurodegeneration. This review presents an overview of signaling by diacylglycerol (DG)-dependent PKC isozymes in the brain, and focuses on the role of the Ca 2+-sensitive conventional PKC isozymes in neurodegeneration.

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          Most cited references98

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          Tau in physiology and pathology.

          Tau is a microtubule-associated protein that has a role in stabilizing neuronal microtubules and thus in promoting axonal outgrowth. Structurally, tau is a natively unfolded protein, is highly soluble and shows little tendency for aggregation. However, tau aggregation is characteristic of several neurodegenerative diseases known as tauopathies. The mechanisms underlying tau pathology and tau-mediated neurodegeneration are debated, but considerable progress has been made in the field of tau research in recent years, including the identification of new physiological roles for tau in the brain. Here, we review the expression, post-translational modifications and functions of tau in physiology and in pathophysiology.
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            AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss.

            Beta amyloid (Abeta), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer's disease. Recent studies indicate that this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Abeta employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Abeta-induced modification of synaptic structure and function.
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              Protein kinase C and other diacylglycerol effectors in cancer.

              Almost three decades after the discovery of protein kinase C (PKC), we still have only a partial understanding of how this family of serine/threonine kinases is involved in tumour promotion. PKC isozymes - effectors of diacylglycerol (DAG) and the main targets of phorbol-ester tumour promoters - have important roles in cell-cycle regulation, cellular survival, malignant transformation and apoptosis. How do PKC isozymes regulate these diverse cellular processes and what are their contributions to carcinogenesis? Moreover, what is the contribution of all phorbol-ester effectors, which include PKCs and small G-protein regulators? We now face the challenge of dissecting the relative contribution of each DAG signal to cancer progression.
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                Author and article information

                Contributors
                Journal
                Neuronal Signal
                Neuronal Signal
                ns
                Neuronal Signaling
                Portland Press Ltd.
                2059-6553
                April 2017
                10 April 2017
                : 1
                : 2
                : NS20160005
                Affiliations
                [1 ]Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0721, U.S.A.
                [2 ]Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093-0721, U.S.A.
                Author notes
                Correspondence: Alexandra C. Newton ( anewton@ 123456ucsd.edu )
                Article
                NS20160005
                10.1042/NS20160005
                7373245
                32714576
                727d1681-9d77-4dab-91d7-060ef99a7d63
                © 2017 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 02 December 2016
                : 02 March 2017
                : 07 March 2017
                : 07 March 2017
                Page count
                Pages: 10
                Categories
                Review Articles
                Molecular Interactions
                Post-Translational Modifications
                Molecular Bases of Health & Disease
                Neuroscience
                Mutation

                alzheimer's disease,neurodegeneration,posttranslational modification,protein kinase c

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