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

Quan Zhang; Haiqiang Dou; Patrik Rorsman

doi:10.1113/jp279775

journal article Open Access Aug 07, 2020

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

Quan Zhang

Haiqiang Dou Patrik Rorsman

The Journal of Physiology Vol. 598 No. 21 pp. 4765-4780 · Wiley

View at Publisher Save 10.1113/jp279775

Abstract

AbstractBy 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.
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Details

Published: Aug 07, 2020
Vol/Issue: 598(21)
Pages: 4765-4780
License: View

Authors

Q

Quan Zhang

Oxford Centre for Diabetes Endocrinology and Metabolism Radcliffe Department of Medicine University of Oxford Churchill Hospital Oxford OX3 7LE UK

H

Haiqiang Dou

Metabolic Physiology Unit Institute of Neuroscience and Physiology University of Göteborg PO Box 430 Göteborg SE‐405 30 Sweden

P

Patrik Rorsman

Oxford Centre for Diabetes Endocrinology and Metabolism Radcliffe Department of Medicine University of Oxford Churchill Hospital Oxford OX3 7LE UK; Metabolic Physiology Unit Institute of Neuroscience and Physiology University of Göteborg PO Box 430 Göteborg SE‐405 30 Sweden

Funding

Vetenskapsrådet

Diabetes UK

Wellcome

Cite This Article

Quan Zhang, Haiqiang Dou, Patrik Rorsman (2020). ‘Resistance is futile?’ – paradoxical inhibitory effects of KATP channel closure in glucagon‐secreting α‐cells. The Journal of Physiology, 598(21), 4765-4780. https://doi.org/10.1113/jp279775

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

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