P. Detimary et al., INTERPLAY BETWEEN CYTOPLASMIC CA2+ AND THE ATP ADP RATIO - A FEEDBACK-CONTROL MECHANISM IN MOUSE PANCREATIC-ISLETS/, Biochemical journal, 333, 1998, pp. 269-274
In pancreatic beta cells, the increase in the ATP/ADP ratio that follo
ws a stimulation by glucose is thought to play an important role in th
e Ca2+-dependent increase in insulin secretion, Here we have investiga
ted the possible interactions between Ca2+ and adenine nucleotides in
mouse islets. Measurements of both parameters in the same single islet
showed that the rise in the ATP/ADP ratio precedes any rise in the cy
toplasmic free-Ca2+ concentration ([Ca2+](i)) and is already present d
uring the initial transient lowering of [Ca2+](i) produced by the suga
r. Blockade of Ca2+ influx with nimodipine did not prevent the concent
ration-dependent increase in the ATP/ADP ratio produced by glucose and
even augmented the ratio at all glucose concentrations which normally
stimulate Ca2+ influx, In contrast, stimulation of Ca2+ influx by 30
mM K+ or 100 mu M tolbutamide lowered the ATP/ADP ratio. This lowering
was of rapid onset and reversibility, sustained and prevented by nimo
dipine or omission of extracellular Ca2+. It was, however, not attenua
ted after blockade of secretion by activation of alpha(2)-adrenoceptor
s. The difference in islet ATP/ADP ratio during blockade and stimulati
on of Ca2+ influx was similar to that observed between threshold and s
ubmaximal glucose concentrations. The results suggest that the followi
ng feedback loop could control the oscillations of membrane potential
and [Ca2+](i) in beta cells. Glucose metabolism increases the ATP/ADP
ratio in a Ca2+-independent manner, which leads to closure of ATP-sens
itive K+ channels, depolarization and stimulation of Ca2+ influx. The
resulting increase in [Ca2+](i) causes a larger consumption than produ
ction of ATP, which induces reopening of ATP-sensitive K+ channels and
arrest of Ca2+ influx. Upon lowering of [Ca2+](i) the ATP/ADP ratio i
ncreases again and a new cycle may start.