Glucose- and arginine-induced insulin secretion by human pancreatic beta-cells: the role of HERG K(+) channels in firing and release.
The human ether-a-go-go-related genes (herg) are expressed in tissues other than heart and brain where the HERG K(+) channels are known to regulate the repolarization of the heart action potential and the neuronal spike-frequency accommodation. We provide evidence that herg1 transcripts are present in human pancreatic islets that were used to study both insulin secretion and electrical activity with radioimmunoassay and single cell perforated patch-clamp techniques, respectively. Glucose- and arginine-induced islets insulin secretion data suggested a net increase of release under perfusion with antiarrhythmic drugs known to selectively block HERG channels. Indeed we could routinely isolate a K(+) current that was recognized as biophysically and pharmacologically similar to the HERG current. An analysis of the glucose- and arginine-induced electrical activity (several applications during 30 min) in terms of firing frequency and putative insulin release was done in control and in the presence of selective blockers of HERG channels: the firing frequency and the release increased by 32% and 77%, respectively. It is concluded that HERG channels have a crucial role in regulating insulin secretion and firing of human beta-cells. This raises the possibility that some genetically characterized hyperinsulinemic diseases of unknown origin might involve mutations in the HERG channels.
Rosati
B
B
Department of Biotechnology and Biosciences, University of Milano-Bicocca, I-20126 Milano, Italy.
Marchetti
P
P
Crociani
O
O
Lecchi
M
M
Lupi
R
R
Arcangeli
A
A
Olivotto
M
M
Wanke
E
E
D018528:ATP-Binding Cassette Transporters; D001120:Arginine / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D054086:KATP Channels; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D011863:Radioimmunoassay; D015203:Reproducibility of Results; D013424:Sulfanilamides / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D000096926:Benzenesulfonamides
D018528:ATP-Binding Cassette Transporters; D001120:Arginine; D001562:Benzimidazoles; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005947:Glucose; D007328:Insulin; D054086:KATP Channels; D011188:Potassium; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D013424:Sulfanilamides; D014044:Tolbutamide; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C072312:ERG protein, human; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; C092520:uK-ATP-1 potassium channel; C073190:WAY 123398; D000096926:Benzenesulfonamides