Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic β cells

Olsen, Henrik Baare; Høy, Marianne; Zhang, Wei; Bertorello, Alejandro M.; Bokvist, Krister; Capito, Kirsten; Efanov, Alexander M.; Meister, Björn; Thams, Peter; Yang, Shao Nian; Rorsman, Patrik; Berggren, Per Olof; Gromada, Jesper

doi:10.1073/pnas.0931282100

Cited by 97 publications

(118 citation statements)

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“…The protein CAPS, which is required for Ca 2ϩ -dependent exocytosis in ␤ cells (20), has been shown to bind PI(4,5)P 2 (21) and may therefore mediate the effects of the lipid on exocytosis. CAPS is expressed in NMRI mouse islets.…”

Section: Resultsmentioning

confidence: 99%

“…PI(4,5)P 2 binds specifically to the Ca 2ϩ -dependent activator protein for secretion (CAPS), which is required for Ca 2ϩ -triggered exocytosis once ATP-dependent priming has been completed (20)(21)(22)(23). In the present study, we have explored the signaling mechanisms by which glucose stimulates PI4K activity in the pancreatic ␤ cell.…”

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confidence: 99%

“…We have recently demonstrated that in ␤ cells, a PI4K serves as a metabolic sensor and, through generation of PI(4,5)P 2 , regulates ATP-dependent priming of secretory granules (20). PI(4,5)P 2 binds specifically to the Ca 2ϩ -dependent activator protein for secretion (CAPS), which is required for Ca 2ϩ -triggered exocytosis once ATP-dependent priming has been completed (20)(21)(22)(23).…”

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Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic β cells through activation of phosphatidylinositol 4-kinase β

Gromada

Bark

Smidt

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Cytosolic free Ca 2؉ plays an important role in the molecular mechanisms leading to regulated insulin secretion by the pancreatic ␤ cell. A number of Ca 2؉ -binding proteins have been implicated in this process. Here, we define the role of the Ca 2؉ -binding protein neuronal Ca 2؉ sensor-1 (NCS-1) in insulin secretion. In pancreatic ␤ 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 ␤ 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 Ca 2؉ -dependent activator protein for secretion present in ␤ cells. Our results provide evidence for an essential role of phosphoinositide synthesis in the regulation of glucose-induced insulin secretion by the pancreatic ␤ cell. We also demonstrate that NCS-1 and its downstream target, PI 4-kinase ␤, are critical players in this process by virtue of their capacity to regulate the release competence of the secretory granules.insulin ͉ phosphoinositides ͉ islet ͉ secretion ͉ Ca 2ϩ -dependent activator protein for secretion N euronal Ca 2ϩ sensor-1 (NCS-1) belongs to the family of EF-hand Ca 2ϩ -binding proteins and is mainly expressed in neuronal and neuroendocrine cells, where it enhances neurotransmission and Ca 2ϩ -dependent exocytosis (1-5). NCS-1 interacts with and regulates the activity of phosphatidylinositol 4-kinase ␤ (PI4K␤) (6-9). The members of the PI4K family catalyze the first step in the synthesis of PI 4,5-bisphosphate [PI(4,5)P 2 ], which has recently emerged as an important regulator of Ca 2ϩ -dependent secretion (10-12). Both a PI transfer protein (13) and a PI4P 5-kinase (14) are required for regulated exocytosis of dense core granules. In addition, the presence of synaptic vesicle and dense core granule-associated PI4K activity is essential for exocytosis (15,16). These data imply that generation of PI(4,5)P 2 is an important step in the event of secretion.In pancreatic ␤ cells, glucose dose-dependently increases ATP levels and decreases ADP levels (16). The resulting rise in the ATP at the expense of ADP is an important regulator of the two major signaling pathways involved in glucose-induced insulin secretion. The first of these pathways uses ATP-sensitive K ϩ channels to couple glucose metabolism with electrical activity, Ca 2ϩ influx, and initiation of insulin secretion. The second pathway is exerted at the level of granule priming and regulates the ␤ cell secretory capacity by modulation of the granules' release competence (17). The ␤ cell contains Ϸ10,000 insulincontaining secretory granules (18). Interestingly, as many as Ϸ5% of the granules are docked below the membrane. The readily releasable pool (RRP), defined by functional measurements, represents a subset (50-100 granules) of the docked pool (19). Granules belongin...

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Section: Resultsmentioning

confidence: 99%

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Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic β cells through activation of phosphatidylinositol 4-kinase β

Gromada

Bark

Smidt

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Phosphatidylinositol-4,5-bisphosphate (PIP 2 ) constitutes only ~1% of the phospholipids in the inner leaflet of the plasma membrane (McLaughlin et al, 2002), but nevertheless plays an important role in secretion by regulating vesicle priming and trafficking (Olsen et al, 2003;Gromada et al, 2005;Waselle et al, 2005) and by serving as precursor for second messengers. One of the best known functions of PIP 2 is as substrate for PLC generation of IP 3 and diacylglycerol (DAG; (Berridge et al, 2000)).…”

Section: Pip 2 and Signalling Via Phospholipase Cmentioning

confidence: 99%

Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

162

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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“…It modulates the functions of a variety of actin regulatory proteins (Yin and Janmey, 2003;Logan and Mandato, 2006) and regulators of exocytotic machinery on the plasma membrane (Olsen et al, 2003;Grishanin et al, 2004;Aoyagi et al, 2005;Li et al, 2006) by directly interacting with its protein targets. In many cases, PtdIns(4,5)P 2 signaling pathways are tightly connected to those of small GTPases belonging to the Rho and Arf families in their upstream and downstream cascades (Santarius et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

TheArabidopsisPhosphatidylinositol Phosphate 5-Kinase PIP5K3 Is a Key Regulator of Root Hair Tip Growth

et al. 2008

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Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P 2 ] functions as a site-specific signal on membranes to promote cytoskeletal reorganization and membrane trafficking. Localization of PtdIns(4,5)P 2 to apices of growing root hairs and pollen tubes suggests that it plays an important role in tip growth. However, its regulation and mode of action remain unclear. We found that Arabidopsis thaliana PIP5K3 (for Phosphatidylinositol Phosphate 5-Kinase 3) encodes a phosphatidylinositol 4-phosphate 5-kinase, a key enzyme producing PtdIns(4,5)P 2 , that is preferentially expressed in growing root hairs. T-DNA insertion mutations that substantially reduced the expression of PIP5K3 caused significantly shorter root hairs than in the wild type. By contrast, overexpression caused longer root hairs and multiple protruding sites on a single trichoblast. A yellow fluorescent protein (YFP) fusion of PIP5K3, driven by the PIP5K3 promoter, complemented the short-root-hair phenotype. PIP5K3-YFP localized to the plasma membrane and cytoplasmic space of elongating root hair apices, to growing root hair bulges, and, notably, to sites about to form root hair bulges. The signal was greatest in rapidly growing root hairs and quickly disappeared when elongation ceased. These results provide evidence that PIP5K3 is involved in localizing PtdIns(4,5)P 2 to the elongating root hair apex and is a key regulator of the machinery that initiates and promotes root hair tip growth.

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Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic β cells

Abstract: Ca 2ϩ -dependent activator protein for secretion (CAPS) ͉ exocytosis ͉ insulin ͉ phosphoinositides

Cited by 97 publications

References 35 publications

Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic β cells through activation of phosphatidylinositol 4-kinase β

Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic β cells through activation of phosphatidylinositol 4-kinase β

Oscillatory control of insulin secretion

TheArabidopsisPhosphatidylinositol Phosphate 5-Kinase PIP5K3 Is a Key Regulator of Root Hair Tip Growth

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