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Protein kinase Cε activation induces EHD-dependent degradation and downregulation of KATP channels: Implications for glucose stimulated insulin secretion

Christopher J Cockcroft, Paul Manna, Rucha Karnik, Tarvinder K Taneja, David Wrighton, Jamel Mankouri, Hong-Lin Rong, Asipu Sivaprasadarao
doi: https://doi.org/10.1101/2020.01.15.907386
Christopher J Cockcroft
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
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Paul Manna
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
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Rucha Karnik
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
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Tarvinder K Taneja
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
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David Wrighton
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
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Jamel Mankouri
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
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Hong-Lin Rong
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
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Asipu Sivaprasadarao
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
†Multidisciplinary Cardiovascular Research Centre, University of Leeds, LS2 9JT, Leeds, U.K
*School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Leeds, U.K
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  • For correspondence: a.sivaprasadarao@leeds.ac.uk
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Abstract

Pancreatic β-cells have the unique ability to couple glucose metabolism to insulin secretion. This capacity is generally attributed to the ability of ATP to inhibit KATP channels, and the consequent β-cell membrane depolarization and excitation. This notion has recently been challenged by a study which demonstrated that high glucose (HG) downregulates the cell surface KATP channels, and thereby leads to β-cell depolarisation and excitation. The authors attributed the downregulation to HG-induced protein kinase C (PKC) activation and the consequent increase in channel endocytosis. This interpretation, however, is inconsistent with our previous findings that PKC activation does not affect endocytosis. To address this controversy, we revisited the problem: we have used cell biological and electrophysiological approaches combined with the pharmacological activator of PKC, PMA (phorbol 12-myristate 13-acetate). We first confirm that PKC does not play a role in KATP channel endocytosis; instead, it downregulates the channel by promoting lysosomal degradation coupled with reduced recycling. We then show that (i) mutation of the dileucine motif (355LL356) in the C-terminal domain of the Kir6.2 subunit of the KATP channel complex prevents lysosomal degradation; (ii) lysosomal targeting is mediated by the EHD (Eps15 homology domain– containing) proteins; and (iii) the PKC isoform responsible for channel degradation is PKCε. Taken together with the published data, we suggest that HG promotes β-cell excitability via two mechanisms: ATP-dependent channel inhibition and ATP-independent, PKCε-dependent channel degradation. The results likely have implications for glucose induced biphasic insulin secretion.

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Posted January 15, 2020.
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Protein kinase Cε activation induces EHD-dependent degradation and downregulation of KATP channels: Implications for glucose stimulated insulin secretion
Christopher J Cockcroft, Paul Manna, Rucha Karnik, Tarvinder K Taneja, David Wrighton, Jamel Mankouri, Hong-Lin Rong, Asipu Sivaprasadarao
bioRxiv 2020.01.15.907386; doi: https://doi.org/10.1101/2020.01.15.907386
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Protein kinase Cε activation induces EHD-dependent degradation and downregulation of KATP channels: Implications for glucose stimulated insulin secretion
Christopher J Cockcroft, Paul Manna, Rucha Karnik, Tarvinder K Taneja, David Wrighton, Jamel Mankouri, Hong-Lin Rong, Asipu Sivaprasadarao
bioRxiv 2020.01.15.907386; doi: https://doi.org/10.1101/2020.01.15.907386

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