[Frontiers in Bioscience S3, 662-679, January 1, 2011]

Studies of first phase insulin secretion using imposed plasma membrane depolarization

Michael Willenborg1, Kathrin Hatlapatka1, Hany Ghaly1, Michael Belz1, Uwe Panten1, Ingo Rustenbeck1

1Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany

TABLE OF CONTENTS

1. Abstract
2. The stimulus secretion-coupling of insulin secretion: substrate site hypothesis vs. receptors site hypothesis
3. The phasic nature of insulin secretion
4. Triggering and amplifying pathways of insulin secretion and their relation with the biphasic kinetics of insulin secretion
5. Consequences of KATP channel block: the unsolved problem of imidazolines
6. Insulin secretion by K+ depolarization: which K+ concentration corresponds to the KATP channel block?
7. Nutrient stimulation of insulin secretion after prior depolarization
8. Signalling role of the action potential for insulin secretion
9. Depolarization by current injection: how to reconcile membrane capacitance measurements with secretion measurements
10. Summary and hypotheses
11. Acknowledgements
12. References

1. ABSTRACT

The first phase of glucose-induced insulin secretion is generally regarded to represent the release of a finite pool of secretion-ready granules, triggered by the depolarization-induced influx of Ca2+ through L-type Ca2+ channels. However, the experimental induction of insulin secretion by imposed plasma membrane depolarization may be more complicated than currently appreciated. A comparison of the effects of high K+ concentrations with those of KATP channel closure, which initiates the electrical activity of the beta cell, suggests that 40 mM K+, which is a popular tool to produce a first phase-like secretion, is of supraphysiological strength, whereas the 20 mV depolarization by 15 mM K+ is nearly inefficient. A major conceptual problem consists in the occurrence of action potentials during KATP channel closure, but not during K+ depolarization, which leaves the K+ channel conductance unchanged. Recent observations suggest that the signal function of the endogenously generated depolarization is not homogeneous, but may rather differ between the component mainly determined by KATP channel closure (slow waves) and that mainly determined by Ca2+ influx (action potentials).