Regulation of large dense-core vesicle volume and neurotransmitter content mediated by adaptor protein 3

Grabner, Chad P.; Price, Steven D.; Lysakowski, Anna; Cahill, Anne L.; Fox, Aaron P.

doi:10.1073/pnas.0509844103

Cited by 60 publications

(48 citation statements)

References 55 publications

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“…Cholesterol-enriched membranes also support SNARE-mediated exocytosis (42), and reduced granule cholesterol content could alter the assembly or function of SNARE complexes. Alternatively, the impaired insulin secretion could reflect retention of a negative regulator of exocytosis during granule maturation (26), particularly since cholesterol contributes to assembly of membrane microdomains during vesicle budding and the granule morphology we observe is similar to that observed in other examples of impaired membrane sorting (43).…”

Section: Discussionsupporting

confidence: 75%

An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells

Sturek¹,

Castle²,

Trace³

et al. 2010

J. Clin. Invest.

136

138

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Cholesterol is a critical component of cell membranes, and cellular cholesterol levels and distribution are tightly regulated in mammals. Recent evidence has revealed a critical role for pancreatic β cell-specific cholesterol homeostasis in insulin secretion as well as in β cell dysfunction in diabetes and the metabolic response to thiazolidinediones (TZDs), which are antidiabetic drugs. The ATP-binding cassette transporter G1 (ABCG1) has been shown to play a role in cholesterol efflux, but its role in β cells is currently unknown. In other cell types, ABCG1 expression is downregulated in diabetes and upregulated by TZDs. Here we have demonstrated an intracellular role for ABCG1 in β cells. Loss of ABCG1 expression impaired insulin secretion both in vivo and in vitro, but it had no effect on cellular cholesterol content or efflux. Subcellular localization studies showed the bulk of ABCG1 protein to be present in insulin granules. Loss of ABCG1 led to altered granule morphology and reduced granule cholesterol levels. Administration of exogenous cholesterol restored granule morphology and cholesterol content and rescued insulin secretion in ABCG1-deficient islets. These findings suggest that ABCG1 acts primarily to regulate subcellular cholesterol distribution in mouse β cells. Furthermore, islet ABCG1 expression was reduced in diabetic mice and restored by TZDs, implicating a role for regulation of islet ABCG1 expression in diabetes pathogenesis and treatment.

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Section: Discussionsupporting

confidence: 75%

An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells

Sturek¹,

Castle²,

Trace³

et al. 2010

J. Clin. Invest.

136

138

View full text Add to dashboard Cite

show abstract

“…[15, 16] Adaptor-related protein complex 3, beta-2 subunit (AP3B2; OMIM #602166) is part of a neuron-specific heterotetrameric vesicle-coat protein complex which is thought to play an important role in neurotransmitter release. [17] However, it is unlikely that deletion of either of these genes is solely responsible for the cognitive deficits seen in 15q25 deletion patients since at least one loss of AP3B2 and at least six losses of CPEB1 have been reported among normal controls in the Database of Genomic Variants (Supplemental Table 6). …”

Section: Discussionmentioning

confidence: 99%

Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond-Blackfan anaemia

Wat

Enciso

Wiszniewski

et al. 2010

Journal of Medical Genetics

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Background Congenital diaphragmatic hernia (CDH) can occur in isolation or in association with other abnormalities. We hypothesized that some cases of non-isolated CDH are caused by novel genomic disorders. Methods and Results In a cohort of >12,000 patients referred for array comparative genomic hybridization testing, we identified three individuals—two of whom had CDH—with deletions involving a ~2.3 Mb region on chromosome 15q25.2. Two additional patients with deletions of this region have been reported, including a fetus with CDH. Clinical data from these patients suggest that recurrent deletions of 15q25.2 are associated with an increased risk of developing CDH, cognitive deficits, cryptorchidism, short stature, and possibly Diamond-Blackfan anemia (DBA). Although no known CDH-associated genes are located on 15q25.2, four genes in this region—CPEB1, AP3B2, HOMER2 and HDGFRP3—have been implicated in CNS development/function and may contribute to the cognitive deficits seen in deletion patients. Deletions of RPS17 may also predispose individuals with 15q25.2 deletions to DBA and associated anomalies. Conclusions Individuals with recurrent deletions of 15q25.2 are at increased risk for CDH and other birth defects. A high index of suspicion should exist for the development of cognitive defects, anemia, and DBA-associated malignancies in these individuals.

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“…Catecholamine secretion from chromaffin cells was monitored by amperometry using carbon-fiber electrodes as described previously (Grabner et al 2006). The electrode was held at ϩ700 mV versus a ground electrode using an NPI VA-10 amplifier to oxidize catecholamine transmitter.…”

Section: Amperometrymentioning

confidence: 99%

Neonatal Intermittent Hypoxia Leads to Long-Lasting Facilitation of Acute Hypoxia-Evoked Catecholamine Secretion From Rat Chromaffin Cells

Souvannakitti

Kumar²,

Fox³

et al. 2009

Journal of Neurophysiology

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Souvannakitti D, Kumar GK, Fox A, Prabhakar NR. Neonatal intermittent hypoxia leads to long-lasting facilitation of acute hypoxia-evoked catecholamine secretion from rat chromaffin cells. J Neurophysiol 101: 2837-2846, 2009. First published April 1, 2009 doi:10.1152/jn.00036.2009. The objective of the present study was to examine the effects of intermittent hypoxia (IH) and sustained hypoxia (SH) on hypoxia-evoked catecholamine (CA) secretion from chromaffin cells in neonatal rats and assess the underlying mechanism(s). Experiments were performed on rat pups exposed to either IH (15-s hypoxia/5-min normoxia; 8 h/day) or SH (hypobaric hypoxia, 0.4 atm) or normoxia (controls) from P0 to P5. IH treatment facilitated hypoxia-evoked CA secretion and elevations in the intracellular calcium ion concentration ([Ca 2ϩ ] i ) and these responses were attenuated, but not abolished, by treatments designed to eliminate Ca 2ϩ flux into cells (Ca 2ϩ -free medium or Cd 2ϩ ), indicating that intracellular Ca 2ϩ stores were augmented by IH. Norepinephrine (NE) and epinephrine (E) levels of adrenal medullae were elevated in IH-treated pups. IH treatment increased reactive oxygen species (ROS) production in adrenal medullae and antioxidant treatment prevented IH-induced facilitation of CA secretion, elevations in [Ca 2ϩ ] i by hypoxia, and the up-regulation of NE and E. The effects of neonatal IH treatment on hypoxia-induced CA secretion and elevation in [Ca 2ϩ ] i , CA, and ROS levels persisted in rats reared under normoxia for Ͼ30 days. In striking contrast, chromaffin cells from SH-treated animals exhibited attenuated hypoxia-evoked CA secretion. In SH-treated cells hypoxiaevoked elevations in [Ca 2ϩ ] i , NE and E contents, and ROS levels were comparable with controls. These observations demonstrate that: 1) neonatal IH and SH evoke opposite effects on hypoxia-evoked CA secretion from chromaffin cells, 2) ROS signaling mediates the faciltatory effects of IH, and 3) the effects of neonatal IH on chromaffin cells persist into adult life. I N T R O D U C T I O NCatecholamine (CA) secretion from the adrenal medulla is critical for maintaining homeostasis under a variety of stress conditions including hypoxia (Lagercrantz and Bistoletti 1977;Seidler and Slotkin 1985). In adult animals, hypoxia-evoked CA secretion from chromaffin cells is neurogenic and requires activation of the sympathetic nervous system (Seidler and Slotkin 1986;Yokotani et al. 2002). In neonates the sympathetic nervous system is not well developed (Seidler and Slotkin 1985). In this case, hypoxia still evokes CA secretion from neonatal chromaffin cells by directly affecting their excitability and elevating intracellular calcium ion concentration ( [Ca 2ϩ ] i ; Takeuchi et al. 2001;Thompson et al. 1997). These studies demonstrate that neonatal chromaffin cells have the ability to sense acute hypoxia similar to the glomus cells of the carotid bodies of adult mammals.Chronic perturbations in environmental O 2 profoundly influence carotid body sensory respo...

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Regulation of large dense-core vesicle volume and neurotransmitter content mediated by adaptor protein 3

Cited by 60 publications

References 55 publications

An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells

An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells

Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond-Blackfan anaemia

Neonatal Intermittent Hypoxia Leads to Long-Lasting Facilitation of Acute Hypoxia-Evoked Catecholamine Secretion From Rat Chromaffin Cells

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