Figure 15.

Glucose stimulates somatostatin secretion through both membrane potential-dependent and -independent pathways. Membrane potential (V_m)–dependent pathway: glucose (large red particles) metabolism increases δ-cell intracellular ATP (green particles) at the expense of ADP and consequently inhibits the K_ATP channels (sensitive to tolbutamide). This leads to membrane depolarization and increase in electrical activity that opens voltage-gated Ca²⁺ channels (VGCC) to allow influx of extracellular Ca²⁺ (blue particles) to increase [Ca²⁺]_i. This exerts a relatively weak stimulation on δ-cell exocytosis (dotted line). V_m-independent pathway: high glucose stimulates somatostatin secretion by promoting CICR in δ-cells. First, the glucose-induced stimulation of ATP production increases ER luminal Ca²⁺ content through SERCA pump. Second, glucose metabolism elevates [cAMP]_i (dark blue particles), a second messenger which activates PKA and Epac2. Whereas PKA directly potentiates δ-cell exocytosis, the effect of Epac2 on exocytosis is mediated through the activation of RYR3 and sensitization of CICR. The cAMP-dependent effects are mimicked by the adenylyl cyclase activator forskolin. The V_m-dependent and -independent pathways operate synergistically leading to a full stimulatory effect of somatostatin secretion by glucose. The key events (increase in ATP/ADP ratio, K_ATP channel closure, action potential firing, increase in [cAMP]_i, CICR, increase in [Ca²⁺]_i, and exocytosis) are highlighted in pink boxes. Green arrows indicate stimulation, and the red blind-ended arrows indicate inhibition. sER, smooth endoplasmic reticulum; GLUT, glucose transporter.