How does glucose evoke electrical activity in the pancreatic beta-cell?
In the absence of glucose, K(ATP) channel activity could be recorded in cell-attached patches. Addition of a sub-stimulatory concentration of glucose (5 mM) was sufficient to completely inhibit K(ATP) channel activity, and raising the glucose concentration to stimulatory levels (12 or 20 mM) had no further effect. Glucose was able to induce electrical activity and insulin release even when K(ATP) channel activity was completely inhibited by 0.5 mM tolbutamide. Glucose-induced electrical and secretory activity were, however, sensitive to inhibition by the anion channel blockers 4,4'-dithiocyanatostilbene-2,2'-disulphonic acid, 5-nitro-2-(3-phenylpropylamino) benzoic acid and 4-hydroxytamoxifen. A 200 pS anion-selective channel was identified in cell-attached patches generating an inward (depolarising) current at 0 mV pipette potential. The channel was activated by glucose over the range 4-20 mM. This channel is likely to be the volume-sensitive anion channel (VSAC) previously described in beta-cells. It is suggested that activation of the VSAC by stimulatory concentrations of glucose is the principal mechanism leading to depolarisation of the plasma membrane and hence electrical activity and insulin release. Channel activation requires glucose metabolism and could involve intracellular accumulation of metabolites and cell swelling. It is possible that the major role of the K(ATP) channel is in hyperpolarizing the cell, thus inhibiting electrical and secretory activity, during hypoglycaemia.
Best
L
L
Department of Medicine, University of Manchester, Oxford Road, Manchester, M13 9WL, UK. lbest@man.ac.uk
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D054086:KATP Channels; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D013629:Tamoxifen; C016601:afimoxifene; D014044:Tolbutamide; D005947:Glucose; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid