ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion

Closure of ATP-regulated K+ channels (KATP channels) plays a central role in glucose-stimulated insulin secretion in beta cells. KATP channels are also highly expressed in glucagon-producing alpha cells, where their function remains unresolved. Under hypoglycaemic conditions, KATP channels are open in alpha cells but their activity is low and only ~1% of that in beta cells. Like beta cells, alpha cells respond to hyperglycaemia with KATP channel closure, membrane depolarisation and stimulation of action potential firing. Yet, hyperglycaemia reciprocally regulates glucagon (inhibition) and insulin secretion (stimulation). Here we discuss how this conundrum can be resolved and how reduced KATP channel activity, via membrane depolarisation, paradoxically reduces alpha cell Ca2+ entry and glucagon exocytosis. Finally, we consider whether the glucagon secretory defects associated with diabetes can be attributed to impaired KATP channel regulation and discuss the potential for remedial pharmacological intervention using sulfonylureas.