Essential role of phosphoinositide 3-kinase in leptin-induced K(ATP) channel activation in the rat CRI-G1 insulinoma cell line

The mechanism by which leptin increases ATP-sensitive K(+) (K(ATP)) channel activity was investigated using the insulin-secreting cell line, CRI-G1. Wortmannin and LY 294002, inhibitors of phosphoinositide 3-kinase (PI3-kinase), prevented activation of K(ATP) channels by leptin. The inositol phospho...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-02, Vol.275 (7), p.4660-4669
Main Authors: Harvey, J, McKay, N.G, Walker, K.S, Kaay, J. van der, Downes, C.P, Ashford, M.L.J
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
cell lines
electric current
electrical conductance
electrophysiology
enzyme activity
enzyme inhibitors
hormonal regulation
hormones
Insulinoma - physiopathology
ion transport
islets of Langerhans
kinases
Leptin - physiology
membrane potential
Mitogen-Activated Protein Kinases - metabolism
neoplasms
Phosphatidylinositol 3-Kinases - metabolism
phosphatidylinositol bisphosphate
phosphatidylinositol trisphosphate
phosphatidylinositols
Phosphatidylinositols - physiology
potassium
Potassium Channels - physiology
Rats
Signal Transduction
Tumor Cells, Cultured
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Summary:The mechanism by which leptin increases ATP-sensitive K(+) (K(ATP)) channel activity was investigated using the insulin-secreting cell line, CRI-G1. Wortmannin and LY 294002, inhibitors of phosphoinositide 3-kinase (PI3-kinase), prevented activation of K(ATP) channels by leptin. The inositol phospholipids phosphatidylinositol bisphosphate and phosphatidylinositol trisphosphate (PtdIns(3,4,5)P(3)) mimicked the effect of leptin by increasing K(ATP) channel activity in whole-cell and inside-out current recordings. LY 294002 prevented phosphatidylinositol bisphosphate, but not PtdIns(3,4,5)P(3), from increasing K(ATP) channel activity, consistent with the latter lipid acting as a membrane-associated messenger linking leptin receptor activation and K(ATP) channels. Signaling cascades, activated downstream from PI 3-kinase, utilizing PtdIns(3,4,5)P(3) as a second messenger and commonly associated with insulin and cytokine action (MAPK, p70 ribosomal protein-S6 kinase, stress-activated protein kinase 2, p38 MAPK, and protein kinase B), do not appear to be involved in leptin-mediated activation of K(ATP) channels in this cell line. Although PtdIns(3,4,5)P(3) appears a plausible and attractive candidate for the messenger that couples K(ATP) channels to leptin receptor activation, direct measurement of PtdIns(3,4,5)P(3) demonstrated that insulin, but not leptin, increased global cellular levels of PtdIns(3,4,5)P(3). Possible mechanisms to explain the involvement of PI 3-kinases in K(ATP) channel regulation are discussed.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.275.7.4660