Synergistic activation of mitogen-activated protein kinase by insulin and adenosine triphosphate in liver cells: permissive role of Ca2+
Abstract
We have previously demonstrated that insulin and G(q)-coupled receptor agonists individually activate mitogen-activated protein kinase (MAPK) in liver cells and both effects involve an influx of extracellular Ca(2+). Yet, these agonists have opposing physiological actions on hepatocyte glucose metabolism. We thus investigated the interaction between insulin and the P2Y(2) purinergic agonist adenosine triphosphate (ATP) on MAPK in HTC cells, a model hepatocyte cell line, and determined the involvement of cytosolic Ca(2+). Insulin and ATP each induced a dose-dependent phosphorylation of p44/42 MAPK that was partially inhibited by EGTA. However, pretreatment with insulin markedly increased the MAPK phosphorylation response to ATP. This potentiation was canceled by chelation of extracellular Ca(2+) with EGTA. We used patch clamp electrophysiology and fluorescence microscopy to understand the role of intracellular Ca(2+) in this effect. Insulin and ATP, respectively, induced monophasic and multiphasic changes in membrane potential and intracellular Ca(2+) as expected. Pretreatment with 10 nmol/L insulin significantly decreased the initial rapid depolarization (inward nonselective cation current [NSCC]), as well as the compounded Ca(...Continue Reading
References
Diabetes induces selective alterations in the expression of protein kinase C isoforms in hepatocytes
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