Inositol 3,4,5,6-Tetrakisphosphate Inhibits Insulin Granule Acidification and Fusogenic Potential

Renström, Erik; Ivarsson, Rosita; Shears, Stephen B.

doi:10.1074/jbc.c200314200

Cited by 35 publications

(31 citation statements)

References 25 publications

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“…The regulation of organelle pH by activation of the NAADP receptor on the vesicle membrane poses exciting questions relating not just to sea urchin biology but also to mammalian biology. Certainly, key enzymes in the lumen of egg vesicles are regulated by pH changes at fertilization (14,38), but in the acidic organelles of mammalian cells, luminal pH influences processes as diverse as secretory vesicle fusion (39), autophagy (40), and proteolysis (41). Our results may have far-reaching implications for NAADP regulating various cellular pathways via pH and not just by Ca 2ϩ .…”

Section: Discussionmentioning

confidence: 89%

Fertilization and Nicotinic Acid Adenine Dinucleotide Phosphate Induce pH Changes in Acidic Ca2+ Stores in Sea Urchin Eggs

Morgan

Galione

2007

Journal of Biological Chemistry

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The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) releases Ca 2؉ from the acidic Ca 2؉ stores of many organisms, including those of the sea urchin egg. We investigated whether the pH within the lumen of these acidic organelles changes in response to stimuli. Fertilization activates the egg by Ca 2؉ release dependent upon NAADP, and accordingly, we report that fertilization also alters organellar pH in a spatio-temporally complex manner. Upon sperm fusion, vesicles deep in the egg center slowly acidify, whereas cortical vesicles undergo a rapid alkalinization. The cortical vesicle alkalinization is independent of exocytosis and cytosolic pH but coincides with the NAADP-dependent fertilization Ca 2؉ wave. Microinjection of NAADP mimicked the fertilization cortical response, suggesting that it occurred within NAADP-sensitive acidic Ca 2؉ stores. Our data show that NAADP and physiological stimuli alter the pH within intracellular organelles and suggest that NAADP signals through pH as well as Ca 2؉ .The sea urchin egg is an invaluable cell model for studying Ca 2ϩ signaling since the discovery of new second messengers and new Ca 2ϩ stores in this system has subsequently proven to have a major impact on mammalian biology (1). The mechanism of activation of the egg upon fertilization encompasses the rapid increases in the cytosolic pH and intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) important for fertilization envelope formation, DNA and protein synthesis, and embryological development (2). The pattern of [Ca 2ϩ ] i changes within the egg are highly organized spatio-temporally and reflect the precisely timed and placed recruitment of different families of Ca 2ϩ channels resident upon either the plasma membrane or intracellular organelles (2, 3). After the initial transient "cortical flash" caused by Ca 2ϩ influx across the plasma membrane (2-5), Ca 2ϩ release from intracellular stores is manifest as a Ca 2ϩ wave that propagates across the entire egg initiating from the point of sperm entry (2). These phasic elevations in [Ca 2ϩ ] i are driven by a complex interplay between the second messengers inositol 1,4,5-trisphosphate, cyclic adenosine diphosphoribose, and nicotinic acid adenine dinucleotide phosphate (NAADP) 2 (1). Importantly, the relative contribution of each messenger to each phase of the Ca 2ϩ signal is different, e.g. NAADP is the only messenger implicated in the cortical flash (4, 5), whereas cyclic adenosine diphosphoribose probably plays a later role in prolonging the main Ca 2ϩ spike (6).NAADP not only evokes a cortical flash but, as first revealed in sea urchin egg, also releases Ca 2ϩ from acidic Ca 2ϩ stores that are lysosome-like organelles (possibly yolk platelets in eggs), whereas inositol 1,4,5-trisphosphate and cyclic adenosine diphosphoribose release Ca 2ϩ from the neutral endoplasmic reticulum (1, 7). Recently in sea urchin egg homogenate, we revealed that the luminal pH (pH L ) of these acidic stores is dynamic and increases upon NAADP-induced Ca 2ϩ release, whic...

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Section: Discussionmentioning

confidence: 89%

Fertilization and Nicotinic Acid Adenine Dinucleotide Phosphate Induce pH Changes in Acidic Ca2+ Stores in Sea Urchin Eggs

Morgan

Galione

2007

Journal of Biological Chemistry

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“…This acidification is considered to be an important step to produce fusion-competent vesicles in the final stages of exocytosis (Hou et al, 2009). This means that Ins(3,4,5,6)P 4 acts to inhibit acidification and, thus, exocytosis (Renström et al, 2002). Two studies showing the importance of the ClC-3 channel for insulin exocytosis were published in Cell Metabolism (Deriy et al, 2009;Li et al, 2009).…”

Section: Higher Inositol Polyphosphatesmentioning

confidence: 99%

New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreaticβ-Cell

Barker

Berggren

2013

Pharmacol Rev

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“…In this way Ins (3,4,5,6)P 4 regulates a range of biological processes, including salt and fluid secretion, neurotransmission, and insulin secretion from pancreatic ␤-cells (8,(11)(12)(13). Recently it was shown that changes in ITPK1 * This work was based on experiments conducted at beamlines 5.0.3 and 5.0.2 of the Advanced Light Source (ALS).…”

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confidence: 99%

Integration of Inositol Phosphate Signaling Pathways via Human ITPK1

Chamberlain

Qian

Stiles

et al. 2007

Journal of Biological Chemistry

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105

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Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a reversible, poly-specific inositol phosphate kinase that has been implicated as a modifier gene in cystic fibrosis. Upon activation of phospholipase C at the plasma membrane, inositol 1,4,5-trisphosphate enters the cytosol and is inter-converted by an array of kinases and phosphatases into other inositol phosphates with diverse and critical cellular activities. In mammals it has been established that inositol 1,3,4-trisphosphate, produced from inositol 1,4,5-trisphosphate, lies in a branch of the metabolic pathway that is separate from inositol 3,4,5,6-tetrakisphosphate, which inhibits plasma membrane chloride channels. We have determined the molecular mechanism for communication between these two pathways, showing that phosphate is transferred between inositol phosphates via ITPK1-bound nucleotide. Intersubstrate phosphate transfer explains how competing substrates are able to stimulate each others' catalysis by ITPK1. We further show that these features occur in the human protein, but not in plant or protozoan homologues. The high resolution structure of human ITPK1 identifies novel secondary structural features able to impart substrate selectivity and enhance nucleotide binding, thereby promoting intersubstrate phosphate transfer. Our work describes a novel mode of substrate regulation and provides insight into the enzyme evolution of a signaling mechanism from a metabolic role.Cellular inositol phosphate metabolism is an intricate web of kinase and phosphatase reactions that produces a number of important signaling molecules (for review see Ref. 1). A now classic example of these signaling activities is the release of Ca 2ϩ into the cytoplasm through an intracellular channel that is gated by inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ) 4 (2). Additional roles are continually being discovered: inositol phosphates have recently been shown to be critical to the activity of RNA-editing enzymes (3), to participate in telomere maintenance (4), and to be the phosphate donors in certain protein phosphorylation events (5). It is of critical interest, therefore, to establish the regulatory mechanisms that govern the metabolism of inositol phosphates.An interesting feature of inositol phosphate metabolism is the promiscuity with which several key kinases phosphorylate multiple substrates (6). For example, ITPK1 (also known as inositol 1,3,4-trisphosphate 5/6-kinase) adds either a 5-or 6-phosphate to Ins(1,3,4)P 3 and also attaches a 1-phosphate to Ins(3,4,5,6)P 4 (6, 7) (inositol phosphate structures shown in Fig. 2). These reactions have been demonstrated to be reversible: ITPK1 can also dephosphorylate Ins(1,3,4,5,6)P 5 back to Ins(3,4,5,6)P 4 (8). An especially puzzling aspect of this phenomenon is that dephosphorylation of Ins(1,3,4,5,6)P 5 by human ITPK1 is stimulated, rather than competitively inhibited, by one of its alternate substrates, Ins(1,3,4)P 3 (8).The fact that mammalian ITPK1 reversibly phosphorylates both Ins(3,4,5,6)P 4 and Ins(1,3,4)P 3 takes on...

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Inositol 3,4,5,6-Tetrakisphosphate Inhibits Insulin Granule Acidification and Fusogenic Potential

Cited by 35 publications

References 25 publications

Fertilization and Nicotinic Acid Adenine Dinucleotide Phosphate Induce pH Changes in Acidic Ca2+ Stores in Sea Urchin Eggs

Fertilization and Nicotinic Acid Adenine Dinucleotide Phosphate Induce pH Changes in Acidic Ca2+ Stores in Sea Urchin Eggs

New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreaticβ-Cell

Integration of Inositol Phosphate Signaling Pathways via Human ITPK1

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