Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic beta cells through activation of phosphatidylinositol 4-kinase beta.
Cytosolic free Ca2+ plays an important role in the molecular mechanisms leading to regulated insulin secretion by the pancreatic beta 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 beta 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 beta 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 beta cells. Our results provide evidence for an essential role of phosphoinositide synthesis in the regulation of glucose-induced insulin secretion by the pancreatic beta cell. We also demonstrate that NCS-1 and its downstream target, PI 4-kinase beta, are critical players in this process by virtue of their capacity to regulate the release competence of the secretory granules.
Gromada
Jesper
J
Lilly Research Laboratories, Essener Bogen 7, D-22419 Hamburg, Germany.
Bark
Christina
C
Smidt
Kamille
K
Efanov
Alexander M
AM
Janson
Juliette
J
Mandic
Slavena A
SA
Webb
Dominic-Luc
DL
Zhang
Wei
W
Meister
Björn
B
Jeromin
Andreas
A
Berggren
Per-Olof
PO
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002458:Cell Fractionation; D002478:Cells, Cultured; D025802:Electric Capacitance; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005089:Exocytosis / Q000502:physiology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D049452:Green Fluorescent Proteins; D015151:Immunoblotting; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D018408:Patch-Clamp Techniques
D002135:Calcium-Binding Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; C485184:enhanced green fluorescent protein; C101464:frequenin calcium sensor proteins; D049452:Green Fluorescent Proteins; D019870:1-Phosphatidylinositol 4-Kinase; D005947:Glucose