Glucose decreases Na+,K+-ATPase activity in pancreatic β-cells. An effect mediated via Ca2+-independent phospholipase A2 and protein kinase C-dependent phosphorylation of the α-subunit

Shigeru Owada, Olof Larsson, Per Arkhammar, Adrian I. Katz, Alexander V. Chibalin, Per Olof Berggren, Alejandro M. Bertorello

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

In the pancreatic β-cell, glucose-induced membrane depolarization promotes opening of voltage-gated L-type Ca2+ channels, an increase in cytoplasmic free Ca2+ concentration ([Ca2+](i)), and exocytosis of insulin. Inhibition of Na+,K+-ATPase activity by ouabain leads to β-cell membrane depolarization and Ca2+ influx. Because glucose-induced β-cell membrane depolarization cannot be attributed solely to closure of ATP- regulated K+ channels, we investigated whether glucose regulates other transport proteins, such as the Na+,K+-ATPase. Glucose inhibited Na+,K+- ATPase activity in single pancreatic islets and intact β-cells. This effect was reversible and required glucose metabolism. The inhibitory action of glucose was blocked by pretreatment of the islets with a selective inhibitor of a Ca2+-independent phospholipase A2. Arachidonic acid, the hydrolytic product of this phospholipase A2, also inhibited Na+,K+-ATPase activity. This effect, like that of glucose, was blocked by nordihydroguaiaretic acid, a selective inhibitor of the lipooxygenase metabolic pathway, but not by inhibitors of the cyclooxygenase or cytochrome P450-monooxyge, nase pathways. The lipooxygenase product 12(S)-HETE (12-S-hydroxyeicosatetranoic acid) inhibited Na+,K+-ATPase activity, and this effect, as well as that of glucose, was blocked by bisindolylmaleimide, a specific protein kinase C inhibitor. Moreover, glucose increased the state of α-subunit phosphorylation by a protein kinase C-dependent process. These results demonstrate that glucose inhibits Na+,K+-ATPase activity in β-cells by activating a distinct intracellular signaling network. Inhibition of Na+,K+-ATPase activity may thus be part of the mechanisms whereby glucose promotes membrane depolarization, an increase in [Ca2+](i), and thereby insulin secretion in the pancreatic β-cell.

Original languageEnglish (US)
Pages (from-to)2000-2008
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number4
DOIs
StatePublished - Jan 22 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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