Voltage-dependent K(+) channels in pancreatic beta cells: role, regulation and potential as therapeutic targets.
Insulin secretion from pancreatic islet beta cells is acutely regulated by a complex interplay of metabolic and electrogenic events. The electrogenic mechanism regulating insulin secretion from beta cells is commonly referred to as the ATP-sensitive K(+) (K(ATP)) channel dependent pathway. Briefly, an increase in ATP and, perhaps more importantly, a decrease in ADP stimulated by glucose metabolism depolarises the beta cell by closing K(ATP) channels. Membrane depolarisation results in the opening of voltage-dependent Ca(2+) channels, and influx of Ca(2+) is the main trigger for insulin secretion. Repolarisation of pancreatic beta cell action potential is mediated by the activation of voltage-dependent K(+) (Kv) channels. Various Kv channel homologues have been detected in insulin secreting cells, and recent studies have shown a role for specific Kv channels as modulators of insulin secretion. Here we review the evidence supporting a role for Kv channels in the regulation of insulin secretion and discuss the potential and the limitations for beta-cell Kv channels as therapeutic targets. Furthermore, we review recent investigations of mechanisms regulating Kv channels in beta cells, which suggest that Kv channels are active participants in the regulation of beta-cell electrical activity and insulin secretion.
MacDonald
P E
PE
Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. p.macdonald@utoronto.ca
Wheeler
M B
MB
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051668:Delayed Rectifier Potassium Channels; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D008954:Models, Biological; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011487:Protein Conformation; D021122:Protein Subunits
D051668:Delayed Rectifier Potassium Channels; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005947:Glucose