Diverse signaling systems activated by the sweet taste receptor in human GLP-1-secreting cells

• Effects of four agonists for the sweet taste receptor were studied in Hutu-80 cells.
• All of the agonists stimulated GLP1 secretion.
• All of four agonists elevated intracellular cyclic AMP.
• Two agonists also increased intracellular Ca2+ while others had opposite effects.
• Sweet taste receptor agonists act as biased agonists in Hutu-80 cells.

Sweet taste receptor regulates GLP-1 secretion in enteroendocrine L-cells. We investigated the signaling system activated by this receptor using Hutu-80 cells. We stimulated them with sucralose, saccharin, acesulfame K and glycyrrhizin. These sweeteners stimulated GLP-1 secretion, which was attenuated by lactisole. All these sweeteners elevated cytoplasmic cyclic AMP ([cAMP]c) whereas only sucralose and saccharin induced a monophasic increase in cytoplasmic Ca2+ ([Ca2+]c). Removal of extracellular calcium or sodium and addition of a Gq/11 inhibitor greatly reduced the [Ca2+]c responses to two sweeteners. In contrast, acesulfame K induced rapid and sustained reduction of [Ca2+]c. In addition, glycyrrhizin first reduced [Ca2+]c which was followed by an elevation of [Ca2+]c. Reductions of [Ca2+]c induced by acesulfame K and glycyrrhizin were attenuated by a calmodulin inhibitor or by knockdown of the plasma membrane calcium pump. These results indicate that various sweet molecules act as biased agonists and evoke strikingly different patterns of intracellular signals.