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J Biol Chem, Vol. 274, Issue 4, 2000-2008, January 22, 1999

Glucose Decreases Na⁺,K⁺-ATPase Activity in Pancreatic -Cells
AN EFFECT MEDIATED VIA Ca²⁺-INDEPENDENT PHOSPHOLIPASE A₂ AND PROTEIN KINASE CDEPENDENT PHOSPHORYLATION OF THE -SUBUNIT

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

From the Rolf Luft Center for Diabetes Research L6B:01, Department of Molecular Medicine, Karolinska Institutet, Karolinska Hospital, S-171 76 Stockholm, Sweden, the  NOVO NORDISK, BioImage, Moerkhoeg Bygade 28, 2860 Soeborg, Denmark, and the ^§ Department of Medicine, University of Chicago, Chicago, Illinois 60637

In the pancreatic -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 -cell membrane depolarization and Ca²⁺ influx. Because glucose-induced -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 -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-monooxygenase 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 -subunit phosphorylation by a protein kinase C-dependent process.

These results demonstrate that glucose inhibits Na⁺,K⁺-ATPase activity in -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 -cell.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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