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

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

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Phosphorylation
Phospholipases A2
Protein Kinase C
Adenosine Triphosphatases
Glucose
Depolarization
Cell membranes
Islets of Langerhans
sodium-translocating ATPase
Cell Membrane
Insulin
Masoprocol
Membranes
Cyclooxygenase Inhibitors
Protein C Inhibitor
Exocytosis
Ouabain
Protein Kinase Inhibitors
Metabolic Networks and Pathways
Arachidonic Acid

ASJC Scopus subject areas

  • Biochemistry

Cite this

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

In: Journal of Biological Chemistry, Vol. 274, No. 4, 22.01.1999, p. 2000-2008.

Research output: Contribution to journalArticle

Owada, Shigeru ; Larsson, Olof ; Arkhammar, Per ; Katz, Adrian I. ; Chibalin, Alexander V. ; Berggren, Per Olof ; Bertorello, Alejandro M. / 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. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 4. pp. 2000-2008.
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AU - Larsson, Olof

AU - Arkhammar, Per

AU - Katz, Adrian I.

AU - Chibalin, Alexander V.

AU - Berggren, Per Olof

AU - Bertorello, Alejandro M.

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