Critical role of gap junction coupled KATP channel activity for regulated insulin secretion.
Pancreatic beta-cells secrete insulin in response to closure of ATP-sensitive K+ (KATP) channels, which causes membrane depolarization and a concomitant rise in intracellular Ca2+ (Cai). In intact islets, beta-cells are coupled by gap junctions, which are proposed to synchronize electrical activity and Cai oscillations after exposure to stimulatory glucose (>7 mM). To determine the significance of this coupling in regulating insulin secretion, we examined islets and beta-cells from transgenic mice that express zero functional KATP channels in approximately 70% of their beta-cells, but normal KATP channel density in the remainder. We found that KATP channel activity from approximately 30% of the beta-cells is sufficient to maintain strong glucose dependence of metabolism, Cai, membrane potential, and insulin secretion from intact islets, but that glucose dependence is lost in isolated transgenic cells. Further, inhibition of gap junctions caused loss of glucose sensitivity specifically in transgenic islets. These data demonstrate a critical role of gap junctional coupling of KATP channel activity in control of membrane potential across the islet. Control via coupling lessens the effects of cell-cell variation and provides resistance to defects in excitability that would otherwise lead to a profound diabetic state, such as occurs in persistent neonatal diabetes mellitus.
Rocheleau
Jonathan V
JV
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Remedi
Maria S
MS
Granada
Butch
B
Head
W Steven
WS
Koster
Joseph C
JC
Nichols
Colin G
CG
Piston
David W
DW
D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002413:Cations, Divalent / Q000737:chemistry; D002478:Cells, Cultured; D017629:Gap Junctions / Q000378:metabolism*; D005947:Glucose; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008564:Membrane Potentials; D008954:Models, Biological; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques
D002413:Cations, Divalent; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C117780:mitochondrial K(ATP) channel; D005947:Glucose; D002118:Calcium