Oscillations of membrane potential and cytosolic Ca(2+) concentration in SUR1(-/-) beta cells

Diabetologia. 2004 Mar;47(3):488-498. doi: 10.1007/s00125-004-1348-0. Epub 2004 Feb 11.

Abstract

Aims/hypothesis: SUR1(ABCC8)(-/-) mice lacking functional K(ATP) channels are an appropriate model to test the significance of K(ATP) channels in beta-cell function. We examined how this gene deletion interferes with stimulus-secretion coupling. We tested the influence of metabolic inhibition and galanin, whose mode of action is controversial.

Methods: Plasma membrane potential (Vm) and currents were measured with microelectrodes or the patch-clamp technique; cytosolic Ca(2+) concentrations ([Ca(2+)](c)) and mitochondrial membrane potential (DeltaPsi) were measured using fluorescent dyes.

Results: In contrast to the controls, SUR1(-/-) beta cells showed electrical activity even at a low glucose concentration. Continuous spike activity was measured with the patch-clamp technique, but with microelectrodes slow oscillations in Vm consisting of bursts of Ca(2+)-dependent action potentials were detected. [Ca(2+)](c) showed various patterns of oscillations or a sustained increase. Sodium azide did not hyperpolarize SUR1(-/-) beta cells. The depolarization of DeltaPsi evoked by sodium azide was significantly lower in SUR1(-/-) than SUR1(+/+) cells. Galanin transiently decreased action potential frequency and [Ca(2+)](c) in cells from both SUR1(-/-) and SUR1(+/+) mice.

Conclusion/interpretation: The strong dependence of Vm and [Ca(2+)](c) on glucose concentration observed in SUR1(+/+) beta cells is disrupted in the knock-out cells. This demonstrates that both parameters oscillate in the absence of functional K(ATP) channels. The lack of effect of metabolic inhibition by sodium azide shows that in SUR1(-/-) beta cells changes in ATP/ADP no longer link glucose metabolism and Vm. The results with galanin suggest that this peptide affects beta cells independently of K(ATP) currents and thus could contribute to the regulation of beta-cell function in SUR1(-/-) animals.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters
  • Action Potentials / physiology
  • Animals
  • Calcium / physiology*
  • Cytosol / metabolism
  • Glucose / pharmacology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / physiology*
  • Kinetics
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multidrug Resistance-Associated Proteins
  • Potassium Channels, Inwardly Rectifying / deficiency
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / physiology*
  • Receptors, Drug
  • Sulfonylurea Receptors

Substances

  • ATP-Binding Cassette Transporters
  • Abcc8 protein, mouse
  • BIK channel
  • Multidrug Resistance-Associated Proteins
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Receptors
  • Glucose
  • Calcium