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

Am J Physiol Endocrinol Metab. 2019 Apr 1;316(4):E646-E659. doi: 10.1152/ajpendo.00342.2018. Epub 2019 Jan 29.

Abstract

Pancreatic α-cells exhibit oscillations in cytosolic Ca2+ (Ca2+c), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate α-cell Ca2+c oscillations have not been elucidated. As β-cell Ca2+c oscillations are regulated in part by Ca2+-activated K+ (Kslow) currents, this work investigated the role of Kslow in α-cell Ca2+ handling and GCG secretion. α-Cells displayed Kslow currents that were dependent on Ca2+ influx through L- and P/Q-type voltage-dependent Ca2+ channels (VDCCs) as well as Ca2+ released from endoplasmic reticulum stores. α-Cell Kslow was decreased by small-conductance Ca2+-activated K+ (SK) channel inhibitors apamin and UCL 1684, large-conductance Ca2+-activated K+ (BK) channel inhibitor iberiotoxin (IbTx), and intermediate-conductance Ca2+-activated K+ (IK) channel inhibitor TRAM 34. Moreover, partial inhibition of α-cell Kslow with apamin depolarized membrane potential ( Vm) (3.8 ± 0.7 mV) and reduced action potential (AP) amplitude (10.4 ± 1.9 mV). Although apamin transiently increased Ca2+ 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 Ca2+ influx. Total α-cell Ca2+c 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 Ca2+c following prolonged Kslow 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 Kslow activation provides a hyperpolarizing influence on α-cell Vm that sustains Ca2+ entry during hypoglycemic conditions, presumably by preventing voltage-dependent inactivation of P/Q-type VDCCs. Thus, when α-cell Ca2+c is elevated during secretagogue stimulation, Kslow activation helps to preserve GCG secretion.

Keywords: calcium handling; glucagon secretion; potassium channel; α-cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • 6,10-diaza-3(1,3),8(1,4)dibenzena-1,5(1,4)diquinolinacyclodecaphane
  • Alkanes
  • Calcium Channels
  • Calcium Channels, L-Type
  • Calcium Channels, P-Type
  • Calcium Channels, Q-Type
  • Peptides
  • Potassium Channel Blockers
  • Potassium Channels, Calcium-Activated
  • Pyrazoles
  • Quinolinium Compounds
  • TRAM 34
  • Apamin
  • iberiotoxin
  • Glucagon
  • Glucose
  • Calcium