The Department of Biomedicine

BBB Seminar: Anders Tengholm

Dynamic imaging of plasma membrane signaling underlying insulin secretion

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Anders Tengholm
Department of Medical Cell Biology, Uppsala University, Sweden

Progress in understanding the complex signaling processes underlying the regulation of various cell functions requires analysis of the spatial and temporal dynamics of second messengers and signaling proteins in individual cells. Pancreatic β-cells have an inherent ability to generate oscillatory signals that trigger insulin release. Coordination of the secretory activity among β-cells results in pulsatile insulin secretion from the pancreas, which is considered important for the action of the hormone in the target tissues. This lecture will focus on the mechanisms underlying glucose-induced pulsatile insulin secretion at the level of the individual β-cell. Ca2+ is the most important trigger of exocytosis and oscillations in membrane potential and Ca2+ influx in β-cells have been well characterized. Real-time total internal reflection fluorescence imaging of β-cells recently demonstrated that glucose and the incretin hormone GLP-1, in addition to triggering Ca2+ signaling, evoke oscillations in the cAMP concentration beneath the plasma membrane, where the nucleotide potently amplifies insulin exocytosis and contribute to pulsatile secretion of insulin. The glucose-induced cAMP signals are relatively independent of changes in the cytoplasmic Ca2+ concentration and are instead governed by variations in cell metabolism. Protein kinase A seems important for the magnitude of first phase and the establishment of a proper second phase secretion, but the kinase is not required for maintaining already manifested pulsatile insulin secretion from glucose-stimulated b‑cells. Instead, the cAMP dependence of glucose-induced pulsatile insulin secretion is mediated by the cAMP-regulated guanine nucleotide exchange factor Epac2. This protein is subject to intricate spatio-temporal regulation and it will be discussed how cAMP and Ca2+ signals are associated with translocation of Epac2 to the plasma membrane.

Host: Stein Ove Døskeland, Department of Biomedicine