Neuronal Calcium Sensor-1 Potentiates Glucose-Dependent Exocytosis in Pancreatic β Cells through Activation of Phosphatidylinositol 4-Kinase β

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-07, Vol.102 (29), p.10303-10308
• Main Authors: Gromada, Jesper, Bark, Christina, Smidt, Kamille, Efanov, Alexander M., Janson, Juliette, Mandic, Slavena A., Webb, Dominic-Luc, Zhang, Wei, Meister, Björn, Jeromin, Andreas, Berggren, Per-Olof, Luft, Rolf
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 4-Kinase - metabolism; 1-Phosphatidylinositol 4-Kinase - physiology; Animals; Antibodies; B lymphocytes; Biological Sciences; Calcium-Binding Proteins - metabolism; Capacitance; Cell Fractionation; Cells, Cultured; Depolarization; Electric Capacitance; Enzyme Activation - physiology; Enzyme-Linked Immunosorbent Assay; Exocytosis; Exocytosis - physiology; Female; Glucose - metabolism; Green Fluorescent Proteins; Immunoblotting; Immunohistochemistry; Insulin - metabolism; Insulin Secretion; Islet cells; Islets of Langerhans - enzymology; Islets of Langerhans - metabolism; Medical Biochemistry; Medicin och hälsovetenskap; Medicinsk biokemi; Mice; Mice, Inbred Strains; Nerve Tissue Proteins - metabolism; Neuronal Calcium-Sensor Proteins; Neuropeptides; Patch-Clamp Techniques; Phosphatidylinositols; Physiological regulation; Secretion; Secretory vesicles
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0504487102

Cytosolic free Ca2+plays an important role in the molecular mechanisms leading to regulated insulin secretion by the pancreatic β cell. A number of Ca2+-binding proteins have been implicated in this process. Here, we define the role of the Ca2+-binding protein neuronal Ca2+sensor-1 (NCS-1) in insulin secretion. In pancreatic β cells, NCS-1 increases exocytosis by promoting the priming of secretory granules for release and increasing the number of granules residing in the readily releasable pool. The effect of NCS-1 on exocytosis is mediated through an increase in phosphatidylinositol (PI) 4-kinase β activity and the generation of phosphoinositides, specifically PI 4-phosphate and PI 4,5-bisphosphate. In turn, PI 4,5-bisphosphate controls exocytosis through the Ca2+-dependent activator protein for secretion present in β cells. Our results provide evidence for an essential role of phosphoinositide synthesis in the regulation of glucose-induced insulin secretion by the pancreatic β cell. We also demonstrate that NCS-1 and its downstream target, PI 4-kinase β, are critical players in this process by virtue of their capacity to regulate the release competence of the secretory granules.