Glucose-mediated inhibition of calcium-activated potassium channels limits α-cell calcium influx and glucagon secretion

Pancreatic α-cells exhibit oscillations in cytosolic Ca (Ca ), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate α-cell Ca oscillations have not been elucidated. As β-cell Ca oscillations are regulated in part by Ca -activated K (K ) currents, this work investig...

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Published in:American journal of physiology: endocrinology and metabolism Vol. 316; no. 4; p. E646
Main Authors: Dickerson, Matthew T, Dadi, Prasanna K, Altman, Molly K, Verlage, Kenneth R, Thorson, Ariel S, Jordan, Kelli L, Vierra, Nicholas C, Amarnath, Gautami, Jacobson, David A
Format: Journal Article
Language:English
Published: United States 01.04.2019
Subjects:
Alkanes - pharmacology
Animals
Apamin - pharmacology
Calcium - metabolism
Calcium Channels - metabolism
Calcium Channels, L-Type - metabolism
Calcium Channels, P-Type - metabolism
Calcium Channels, Q-Type - metabolism
Endoplasmic Reticulum - metabolism
Glucagon - metabolism
Glucagon-Secreting Cells - metabolism
Glucose - metabolism
Mice
Mice, Transgenic
Patch-Clamp Techniques
Peptides - pharmacology
Potassium Channel Blockers - pharmacology
Potassium Channels, Calcium-Activated - antagonists & inhibitors
Potassium Channels, Calcium-Activated - metabolism
Pyrazoles - pharmacology
Quinolinium Compounds - pharmacology
potassium channel
α-cell
calcium handling
glucagon secretion
ISSN:1522-1555, 1522-1555
Online Access:Get more information
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Summary:Pancreatic α-cells exhibit oscillations in cytosolic Ca (Ca ), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate α-cell Ca oscillations have not been elucidated. As β-cell Ca oscillations are regulated in part by Ca -activated K (K ) currents, this work investigated the role of K in α-cell Ca handling and GCG secretion. α-Cells displayed K currents that were dependent on Ca influx through L- and P/Q-type voltage-dependent Ca channels (VDCCs) as well as Ca released from endoplasmic reticulum stores. α-Cell K was decreased by small-conductance Ca -activated K (SK) channel inhibitors apamin and UCL 1684, large-conductance Ca -activated K (BK) channel inhibitor iberiotoxin (IbTx), and intermediate-conductance Ca -activated K (IK) channel inhibitor TRAM 34. Moreover, partial inhibition of α-cell K with apamin depolarized membrane potential ( V ) (3.8 ± 0.7 mV) and reduced action potential (AP) amplitude (10.4 ± 1.9 mV). Although apamin transiently increased Ca influx into α-cells at low glucose (42.9 ± 10.6%), sustained SK (38.5 ± 10.4%) or BK channel inhibition (31.0 ± 11.7%) decreased α-cell Ca influx. Total α-cell Ca was similarly reduced (28.3 ± 11.1%) following prolonged treatment with high glucose, but it was not decreased further by SK or BK channel inhibition. Consistent with reduced α-cell Ca following prolonged K inhibition, apamin decreased GCG secretion from mouse (20.4 ± 4.2%) and human (27.7 ± 13.1%) islets at low glucose. These data demonstrate that K activation provides a hyperpolarizing influence on α-cell V that sustains Ca entry during hypoglycemic conditions, presumably by preventing voltage-dependent inactivation of P/Q-type VDCCs. Thus, when α-cell Ca is elevated during secretagogue stimulation, K activation helps to preserve GCG secretion.
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ISSN:1522-1555
1522-1555
DOI:10.1152/ajpendo.00342.2018