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Erschienen in:
01.05.2005 | Article
Crosstalk between membrane potential and cytosolic Ca2+ concentration in beta cells from Sur1 −/− mice
Erschienen in: Diabetologia | Ausgabe 5/2005
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Aims/hypothesis
Islets or beta cells from Sur1
−/−
mice were used to determine whether changes in plasma membrane potential (V
m) remain coupled to changes in cytosolic Ca2+ ([Ca2+]i) in the absence of KATP channels and thus provide a triggering signal for insulin secretion. The study also sought to elucidate whether [Ca2+]i influences oscillations in V
m in sur1−/− beta cells.
Methods
Plasma membrane potential and ion currents were measured with microelectrodes and the patch–clamp technique. [Ca2+]i was monitored with the fluorescent dye fura-2. Insulin secretion from isolated islets was determined by static incubations.
Results
Membrane depolarisation of Sur1−/− islets by arginine or increased extracellular K+, elevated [Ca2+]i and augmented insulin secretion. Oligomycin completely abolished glucose-stimulated insulin release from Sur1−/− islets. Oscillations in V
m were influenced by [Ca2+]i as follows: (1) elevation of extracellular Ca2+ lengthened phases of membrane hyperpolarisation; (2) simulating a burst of action potentials induced a Ca2+-dependent outward current that was augmented by increased Ca2+ influx through L-type Ca2+ channels; (3) Ca2+ depletion of intracellular stores by cyclopiazonic acid increased the burst frequency in Sur1−/− islets, elevating [Ca2+]i and insulin secretion; (4) store depletion activated a Ca2+ influx that was not inhibitable by the L-type Ca2+ channel blocker D600.
Conclusions/interpretation
Although V
m is largely uncoupled from glucose metabolism in the absence of KATP channels, increased electrical activity leads to elevations of [Ca2+]i that are sufficient to stimulate insulin secretion. In Sur1−/− beta cells, [Ca2+]i exerts feedback mechanisms on V
m by activating a hyperpolarising outward current and by depolarising V
m via store-operated ion channels.