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Glucose-induced increase of cytoplasmic Ca2+ in pancreatic beta-cells is usually manifested as slow oscillations from the basal level. The significance of this rhythmicity for maintaining normal beta-cell function with periodic variations of circulating insulin made it of interest to investigate how the oscillatory Ca2+ signal was affected by various amino acids. Individual mouse beta-cells were very sensitive to alanine, glycine and arginine, sometimes responding with a transformation of the oscillations into sustained elevation of cytoplasmic Ca2+ at amino acid concentrations as low as 0.1 mM. Stimulation of the entry of Ca2+, obtained either by raising the extracellular concentration or by prolonging the open state of the voltage-dependent Ca2+ channels with BAY K 8644, resulted in reappearance of the rhythmic activity in the presence of the amino acids. Oscillatory Ca2+ signals in intact islets were more resistant to transformation by amino acids than those of individual beta-cells. It is therefore suggested that signals from the adjacent cells make it possible for beta-cells situated in islets to overcome a suppression of the oscillatory activity otherwise seen in the presence of alanine, glycine or arginine.
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External ATP is supposed to trigger short-lived increases (transients) of cytoplasmic Ca2+ important for entraining insulin-secreting β-cells into a common rhythm. To get insight into this process, rises of the cytoplasmic Ca2+ concentration ([Ca2+]i) induced by external ATP were compared with those obtained with acetylcholine, another neurotransmitter with stimulatory effects on the inositol trisphosphate (IP3) production. A ratiometric fura-2 technique was used for measuring [Ca2+]i in individual β-cells and small aggregates isolated from ob/ob mouse islets and superfused with a medium containing methoxyverapamil. ATP and acetylcholine induced temporary rises of [Ca2+]I from a basal level manifested as solitary transients (<20 s) and bumps (≥20 s) superimposed or not with transients. Addition of ATP (1–100 μM) usually triggered transients whereas acetylcholine induced bumps lacking superimposed transients. After the initial rise there was a steady-state elevation of [Ca2+]i in β-cells exposed to acetylcholine but not to ATP. Similar differences were seen comparing the responses of rat β-cells to 100 μM ATP and acetylcholine. Inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump (with 50 μM cyclopiazonic acid) prevented both the ATP-induced rise of [Ca2+]i and the spontaneous firing of transients. Similar effects were seen after activation of protein kinase C (10 nM phorbol-12-myristate-13-acetate), whereas an inhibitor of this enzyme (2 μM bisindolylmaleimide) promoted the generation of transients. The results indicate that ATP fulfils the demands for a coordinator of the secretory activity of β-cells by generating distinct [Ca2+]i transients without sustained elevation of basal [Ca2+]i.
