‘Resistance is futile?’ – paradoxical inhibitory effects of KATP channel closure in glucagon-secreting α-cells

Quan Zhang, Haiqiang Dou, Patrik Rorsman

Research output: Contribution to journalReview articlepeer-review

16 Citations (Scopus)
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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 (KATP) channels that are regulated by the intracellular ATP/ADP ratio. In β-cells, KATP channels are active at low (non-insulin-releasing) glucose concentrations. An increase in glucose leads to KATP channel closure, membrane depolarization and electrical activity that culminates in elevation of [Ca2+]i and initiation of exocytosis of the insulin-containing secretory granules. The α-cells are also equipped with KATP 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 Ca2+-dependent action potentials. Closure of residual KATP 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 Ca2+ 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. (Figure presented.).

Original languageEnglish
Pages (from-to)4765-4780
Number of pages16
JournalJournal of Physiology
Issue number21
Early online date27 Jul 2020
Publication statusPublished (in print/issue) - 30 Oct 2020

Bibliographical note

Funding Information:
Supported by Diabetes UK (QZ), the Swedish Research Council (PR) and the Helmsley Trust (PR). Concepts presented in this Topical Review are based on studies supported by the Wellcome Trust.

Publisher Copyright:
© 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society


  • diabetes
  • glucagon
  • insulin
  • K channels
  • membrane potential


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