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Evidence for glucagon-like peptide-1 receptor signaling to activate ATP-sensitive potassium channels in pancreatic beta cells

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Affiliated Author(s)
박재형송대규조호찬
Alternative Author(s)
Park, Jae HyungSong, Dae KyuCho, Ho Chan
Journal Title
Biochemical and biophysical research communications.
ISSN
0006-291X
Issued Date
2016
Keyword
Glucagon-like peptide-1Phosphoinositide 3-kinasePancreatic beta cellGlucagon-like peptide-1 receptorATP-sensitive potassium channel
Abstract
Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic beta cells.
GLP-1 has been shown to confer glucose-insensitive beta cells with glucose sensitivity by modulation of
the activity of the ATP-sensitive potassium (KATP) channel. The channel closing effect of GLP-1, interacting
with corresponding G-protein-coupled receptors, has been well established; however, to our knowledge,
no study has shown whether GLP-1 directly induces activation of beta-cell KATP channels. Here, we aimed
to evaluate whether the activation of beta-cell KATP channels by GLP-1 exists and affects intracellular
Ca2þ levels ([Ca2þ]i). KATP channel activity was measured in isolated rat pancreatic beta cells by wholecell
perforated patch-clamp recordings with a diazoxide-containing pipette solution. Changes in [Ca2þ]i
and the subcellular localization of KATP channels were observed using the calcium-sensitive dye fura-4/
AM and anti-Kir6.2 antibodies in INS-1 beta cells, respectively. To eliminate the well-known inhibitory
effects of GLP-1 on KATP channel activity, channels were fully inhibited by pretreatment with methyl
pyruvate and epigallocatechin-3-gallate. In the pretreated beta cells, GLP-1 and exendin-4 promptly
activated the channels, reducing [Ca2þ]i. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002
blocked the effects of GLP-1 on channel activity. Moreover, phosphatidylinositol-3,4,5-trisphosphate
mimicked the effects of GLP-1. These results suggested that beta-cell GLP-1 receptor signaling
involved activation of KATP channels via a PI3K-dependent pathway. This alternative mechanism of GLP-1
function may act as a negative feedback pathway, modulating the glucose-dependent GLP-1 inhibition on
KATP channel activity.
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