The endoplasmic reticulum plays a key role in α-cell intracellular Ca²⁺ dynamics and glucose-regulated glucagon...

Glucagon is secreted by pancreatic α-cells to counteract hypoglycaemia. How glucose regulates glucagon secretion remains unclear. Here, using mouse islets, we studied the role of transmembrane and endoplasmic reticulum (ER) Ca²⁺ on intrinsic α-cell glucagon secretion. Blocking isradipine-sensitive L-type voltage-gated Ca²⁺ (Ca_v) channels abolished α-cell electrical activity but had little impact on its cytosolic Ca²⁺ oscillations or low-glucose-stimulated glucagon secretion. In contrast, depleting ER Ca²⁺ with cyclopiazonic acid or blocking ER Ca²⁺-releasing ryanodine receptors abolished α-cell glucose sensitivity and low-glucose-stimulated glucagon secretion. ER Ca²⁺ mobilization in α-cells is regulated by intracellular ATP and likely to be coupled to Ca²⁺ influx through P/Q-type Ca_v channels. ω-Agatoxin IVA blocked α-cell ER Ca²⁺ release and cell exocytosis, but had no additive effect on glucagon secretion when combined with ryanodine. We conclude that glucose regulates glucagon secretion through the control of ER Ca²⁺ mobilization, a mechanism that can be independent of α-cell electrical activity.