Intestinal enteroendocrine cells rely on ryanodine and IP 3 calcium store receptors for mechanotransduction

作者：Kaitlyn R. Knutson, Sara Whiteman, Constanza Alcaino, Arnaldo Mercado‐Perez, Isabelle W. Finholm, Hannah K. Serlin, Shreya S. Bellampalli, David R. Linden, Gianrico Farrugia, Arthur Beyder · 发表于：The Journal of Physiology · 年份：2022 · DOI：10.1113/jp283383 · 被引用次数：26 · 研究领域：Erythrocyte Function and Pathophysiology、Ion channel regulation and function、Pancreatic function and diabetes

Abstract Enteroendocrine cells (EECs) are specialized sensors of luminal forces and chemicals in the gastrointestinal (GI) epithelium that respond to stimulation with a release of signalling molecules such as serotonin (5‐HT). For mechanosensitive EECs, force activates Piezo2 channels, which generate a very rapidly activating and inactivating (∼10 ms) cationic (Na + , K + , Ca 2+ ) receptor current. Piezo2 receptor currents lead to a large and persistent increase in intracellular calcium (Ca 2+ ) that lasts many seconds to sometimes minutes, suggesting signal amplification. However, intracellular calcium dynamics in EEC mechanotransduction remain poorly understood. The aim of this study was to determine the role of Ca 2+ stores in EEC mechanotransduction. Mechanical stimulation of a human EEC cell model (QGP‐1) resulted in a rapid increase in cytoplasmic Ca 2+ and a slower decrease in ER stores Ca 2+ , suggesting the involvement of intracellular Ca 2+ stores. Comparing murine primary colonic EECs with colonocytes showed expression of intercellular Ca 2+ store receptors, a similar expression of IP 3 receptors, but a >30‐fold enriched expression of Ryr3 in EECs. In mechanically stimulated primary EECs, Ca 2+ responses decreased dramatically by emptying stores and pharmacologically blocking IP 3 and RyR1/3 receptors. RyR3 genetic knockdown by siRNA led to a significant decrease in mechanosensitive Ca 2+ responses and 5‐HT release. In tissue, pressure‐induced increase in the U...