Low glucose-induced ghrelin secretion is mediated by an ATP-sensitive potassium channel

Ghrelin is synthesized in X/A-like cells of the gastric mucosa, which plays an important role in the regulation of energy homeostasis. Although ghrelin secretion is known to be induced by neurotransmitters or hormones or by nutrient sensing in the ghrelin-secreting cells themselves, the mechanism of ghrelin secretion is not clearly understood. In the present study, we found that changing the extracellular glucose concentration from elevated (25 mM) to optimal (10 mM) caused an increase in the intracellular Ca2+ concentration ([Ca2+](i)) in ghrelin-secreting mouse ghrelinoma 3-1 (MGN3-1) cells (n = 32, P < 0.01), whereas changing the glucose concentration from elevated to lowered (5 or 1 mM) had little effect on [Ca2+](i) increase. Overexpression of a closed form of an ATP-sensitive K+ (K-ATP) channel mutant suppressed the 10 mM glucose-induced [Ca2+](i) increase (n = 8, P < 0.01) and exocytotic events (n = 6, P < 0.01). We also found that a low concentration of a K-ATP channel opener, diazoxide, with 25 mM glucose induced [Ca2+](i) increase (n=23, P < 0.01) and ghrelin secretion (n >= 3, P < 0.05). In contrast, the application of a low concentration of a K-ATP channel blocker, tolbutamide, significantly induced [Ca2+](i) increase (n = 15, P < 0.01) and ghrelin secretion (n >= 3, P < 0.05) under 5 mM glucose. Furthermore, the application of voltage-dependent Ca2+ channel inhibitors suppressed the 10 mM glucose-induced [Ca2+](i) increase (n >= 26, P < 0.01) and ghrelin secretion (n >= 5, P < 0.05). These findings suggest that K-ATP and voltage-dependent Ca2+ channels are involved in glucose-dependent ghrelin secretion in MGN3-1 cells.