Feedback Control of the ATP-Sensitive K+ Current by Cytosolic Ca2+ Contributes to Oscillations of the Membrane Potential in Pancreatic β-Cells
During glucose stimulation, pancreatic β-cells display membrane potential oscillations that correspond to intermittent Ca2+ influx, leading to oscillations of the cytosolic free calcium concentration ([Ca2+]c) and insulin secretion. The role of ATP-sensitive K+ (K+-ATP) channels in the control of these oscillations was investigated by measuring the K+-ATP current (IKATP) with the perforated mode of the patch-clamp technique. No oscillations of IKATP were observed when glucose-stimulated β-cells were kept hyperpolarized, thus with low and stable [Ca2+]c. However, increasing [Ca2+]c by Ca2+ influx (depolarizing pulses) or Ca2+ mobilization (acetylcholine) transiently augmented IKATP. This effect was abolished by tolbutamide, attenuated by increasing the glucose concentration in the medium, and prevented by abrogation of the [Ca2+]c rise, which demonstrates that the current is really IKATP and that its increase is Ca2+-dependent. Injection of a current of a similar amplitude to that of the Ca2+-induced increase in IKATP was sufficient to repolarize glucose-stimulated β-cells. These results suggest that, in the absence of [Ca2+]c oscillations, no metabolic oscillations affect IKATP in pancreatic β-cells. In contrast, [Ca2+]c oscillations evoke IKATP oscillations. This mechanism may constitute the feedback loop controlling the glucose-induced oscillating electrical activity in β-cells.
Address correspondence and reprint requests to Dr. Patrick Gilon, Unité d’Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, UCL 55.30, Av. Hippocrate 55, B-1200 Brussels, Belgium. E-mail:.
Received for publication 2 July 2001 and accepted in revised form 29 October 2001.
ACh, acetylcholine; [Ca2+]c, cytosolic free Ca2+ concentration; IKATP, K+-ATP current; IP3, Ins(1,4,5)P3; K+-ATP channel, ATP-sensitive K+ channel; PIP2, phosphatidylinositol 4,5-bisphosphate.