‘Resistance is futile?’ – paradoxical inhibitory effects of K(ATP) channel closure in glucagon‐secreting α‐cells

By secreting insulin and glucagon, the β‐ and α‐cells of the pancreatic islets play a central role in the regulation of systemic metabolism. Both cells are equipped with ATP‐regulated potassium (K(ATP)) channels that are regulated by the intracellular ATP/ADP ratio. In β‐cells, K(ATP) channels are active at low (non‐insulin‐releasing) glucose concentrations. An increase in glucose leads to K(ATP) channel closure, membrane depolarization and electrical activity that culminates in elevation of [Ca(2+)](i) and initiation of exocytosis of the insulin‐containing secretory granules. The α‐cells are also equipped with K(ATP) channels but they are under strong tonic inhibition at low glucose, explaining why α‐cells are electrically active under hypoglycaemic conditions and generate large Na(+)‐ and Ca(2+)‐dependent action potentials. Closure of residual K(ATP) channel activity leads to membrane depolarization and an increase in action potential firing but this stimulation of electrical activity is associated with inhibition rather than acceleration of glucagon secretion. This paradox arises because membrane depolarization reduces the amplitude of the action potentials by voltage‐dependent inactivation of the Na(+) channels involved in action potential generation. Exocytosis in α‐cells is tightly linked to the opening of voltage‐gated P/Q‐type Ca(2+) channels, the activation of which is steeply voltage‐dependent. Accordingly, the inhibitory effect of the reduced action potential amplitude exceeds the stimulatory effect resulting from the increased action potential frequency. These observations highlight a previously unrecognised role of the action potential amplitude as a key regulator of pancreatic islet hormone secretion. [Image: see text]