Glucose and Pharmacological Modulators of ATP-Sensitive K(+) Channels Control [Ca(2+)](c) by Different Mechanisms in Isolated Mouse α-Cells

OBJECTIVE—We studied how glucose and ATP-sensitive K(+) (K(ATP)) channel modulators affect α-cell [Ca(2+)](c). RESEARCH DESIGN AND METHODS—GYY mice (expressing enhanced yellow fluorescent protein in α-cells) and NMRI mice were used. [Ca(2+)](c), the K(ATP) current (I(KATP), perforated mode) and cell metabolism [NAD(P)H fluorescence] were monitored in single α-cells and, for comparison, in single β-cells. RESULTS—In 0.5 mmol/l glucose, [Ca(2+)](c) oscillated in some α-cells and was basal in the others. Increasing glucose to 15 mmol/l decreased [Ca(2+)](c) by ∼30% in oscillating cells and was ineffective in the others. α-Cell I(KATP) was inhibited by tolbutamide and activated by diazoxide or the mitochondrial poison azide, as in β-cells. Tolbutamide increased α-cell [Ca(2+)](c), whereas diazoxide and azide abolished [Ca(2+)](c) oscillations. Increasing glucose from 0.5 to 15 mmol/l did not change I(KATP) and NAD(P)H fluorescence in α-cells in contrast to β-cells. The use of nimodipine showed that L-type Ca(2+) channels are the main conduits for Ca(2+) influx in α-cells. γ-Aminobutyric acid and zinc did not decrease α-cell [Ca(2+)](c), and insulin, although lowering [Ca(2+)](c) very modestly, did not affect glucagon secretion. CONCLUSIONS—α-Cells display similarities with β-cells: K(ATP) channels control Ca(2+) influx mainly through L-type Ca(2+) channels. However, α-cells have distinct features from β-cells: Most K(ATP) channels are already closed at low glucose, glucose does not affect cell metabolism and I(KATP), and it slightly decreases [Ca(2+)](c). Hence, glucose and K(ATP) channel modulators exert distinct effects on α-cell [Ca(2+)](c). The direct small glucose-induced drop in α-cell [Ca(2+)](c) contributes likely only partly to the strong glucose-induced inhibition of glucagon secretion in islets.