Rapid kinetic measurements of 45Ca2+ mobilization reveal that Ins(2,4,5)P3 is a partial agonist at hepatic InsP3 receptors

Marchant, Jonathan S.; Chang, Young Tae; Chung, Sung Kee; Irvine, Robin F.; Taylor, Colin W.

doi:10.1042/bj3210573

Cited by 38 publications

(24 citation statements)

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“…Ins(1,4,5)P 3 in Ca 2ϩ influx and PtdIns(3,4,5)P 3 in activating the Akt/protein kinase B pathway), the exact roles of many others are continuously being defined. For example, both Ins(2,4,5)P 3 and Ins(1,3,4,5)P 4 have been proposed to potentiate the Ca 2ϩ -mobilizing effects of Ins(1,4,5)P 3 and Ca 2ϩ entry into cells (2,27,29,30). Recent advances have revealed that several inositol polyphosphates (InsP 4 , InsP 5 , and InsP 6 ) can modulate the activities of chromatin-remodeling complexes (31,32), and Ins(1,3,4,5,6)P 5 may serve as a proliferative signal (33).…”

Section: Resultsmentioning

confidence: 99%

Comparative Mechanistic and Substrate Specificity Study of Inositol Polyphosphate 5-Phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2

Chi

Zhou

Wang

et al. 2004

Journal of Biological Chemistry

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Inositol-5-phosphatases are important enzymes involved in the regulation of diverse cellular processes from synaptic vesicle recycling to insulin signaling. We describe a comparative study of two representative inositol-5-phosphatases, Schizosaccharomyces pombe synaptojanin (SPsynaptojanin) and human SH2 domaincontaining inositol-5-phosphatase SHIP2. We show that in addition to Mg 2؉ , transition metals such as Mn 2؉ , Co 2؉ , and Ni 2؉ are also effective activators of SPsynaptojanin. In contrast, Ca 2؉ and Cu 2؉ are inhibitory. We provide evidence that Mg 2؉ binds the same site occupied by Ca 2؉ observed in the crystal structure of SPsynaptojanin complexed with inositol 1,4-bisphosphate (Ins(1,4)P 2 ). Ionizations important for substrate binding and catalysis are defined for the SPsynaptojanin-catalyzed Ins(1,4,5)P 3 reaction. Kinetic analysis with four phosphatidylinositol lipids bearing a 5-phosphate and 54 water-soluble inositol phosphates reveals that SPsynaptojanin and SHIP2 possess much broader substrate specificity than previously appreciated. The rank order for SPsynaptojanin is Ins(2,4,5)P 3 > phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 ) Ϸ Ins(4,5)P 2 Ϸ Ins(1,4,5)P 3 Ϸ Ins(4,5,6)P 3 > PtdIns(3,5)P 2 Ϸ PtdIns(3,4,5)P 3 Ϸ Ins(1,2,4,5)P 4 Ϸ Ins(1,3,4,5)P 4 Ϸ Ins-(2,4,5,6)P 4 Ϸ Ins(1,2,4,5,6)P 5 . The rank order for SHIP2 is Ins(1,2,3,4,5)P 5 > Ins(1,3,4,5)P 4 > PtdIns(3,4,5)P 4 Ϸ PtdIns(3,5)P 2 Ϸ Ins(1,4,5,6)P 4 Ϸ Ins(2,4,5,6)P 4 . Because inositol phosphate isomers elicit different biological activities, the extended substrate specificity for SPsynaptojanin and SHIP2 suggest that these enzymes likely have multiple roles in cell signaling and may regulate distinct pathways. The unique substrate specificity profiles and the importance of 2-position phosphate in binding also have important implications for the design of potent and selective SPsynaptojanin and SHIP2 inhibitors for pharmacological investigation.Eukaryotic cells contain both water-soluble inositol phosphates and the corresponding phosphoinositide lipids. These molecules reside in different cellular compartments and regulate the localization and activity of proteins through their interaction with specific binding domains. Inositol and phosphatidylinositol phosphates are key modulators of cellular processes including signal transduction, cell proliferation, and apoptosis, vesicle trafficking, cell motility and cytoskeletal organization, and transcription (1-5). The best known inositolbased signaling pathway is the cell surface receptor-triggered hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns-(4,5)P 2 )1 by phospholipase C to yield the second messengers inositol 1,4,5-triphosphate (Ins(1,4,5)P 3 ), a regulator of Ca 2ϩ release, and diacylglycerol, an activator of protein kinase C. The activity of the inositol-based molecules depends on which site(s) on the inositol ring is phosphorylated, and the level of phosphorylation is maintained by the combined action of a host of inositol kinases and phosphatases. Although consider...

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Section: Resultsmentioning

confidence: 99%

Comparative Mechanistic and Substrate Specificity Study of Inositol Polyphosphate 5-Phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2

Chi

Zhou

Wang

et al. 2004

Journal of Biological Chemistry

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“…At the purified InsP 3 R1, adenophostin B is about 10 times more potent than InsP 3 (EC 50 values: 11 nM versus 100 nM) and exhibits a positive cooperativity in binding that is not observed with InsP 3 (Hirota et al, 1995). Adenophostin A is also about a 10-fold more potent Ca 2ϩ releaser than InsP 3 in permeabilized hepatocytes (Marchant et al, 1997b;Beecroft et al, 1999) that have predominance of InsP 3 R2 versus InsP 3 R1 (Ͼ80% versus Ͻ20%) (Wojcikiewicz, 1995;De Smedt et al, 1997).…”

Section: Pharmacological Modulation Of Smooth Muscle Srmentioning

confidence: 97%

Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle

Laporte

Hui

Laher

2004

Pharmacological Reviews

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“…2), in the presence of Ca 2ϩ entry some refilling of the stores occurs. We consider the latter alternative the more likely because previous studies have shown that (2,4,5)IP 3 acts as a partial agonist compared with (1,4,5)IP 3 when rate of release rather than extent of release is measured (23 (Table I and Fig. 3).…”

Section: Fig 8 Adenophostin-induced Current Responses In a Stronglymentioning

confidence: 99%

Effect of Adenophostin A on Ca2+ Entry and Calcium Release-activated Calcium Current (I crac) in Rat Basophilic Leukemia Cells

Huang¹,

Takahashi²,

Tanzawa³

et al. 1998

Journal of Biological Chemistry

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In most non-excitable cells, calcium influx is signaled by depletion of intracellular calcium stores, a process known as capacitative calcium entry. Adenophostin A, a potent activator of the inositol 1,4,5-trisphosphate receptor, has been reported to activate Ca 2؉ entry in Xenopus oocytes to a greater extent than expected on the basis of its ability to release calcium stores. In this study, we compared the abilities of adenophostin A and inositol 2,4,5-trisphosphate ((2,4,5)IP 3 Stimulation of G-protein-coupled receptors and tyrosine kinase receptors activates phospholipase C, which generates inositol 1,4,5-trisphosphate ((1,4,5)IP 3 ) 1 and diacylglycerol.(1,4,5)IP 3 binds to its receptor on the membrane of the endoplasmic reticulum and releases Ca 2ϩ stored therein. The depletion of intracellular Ca 2ϩ stores then signals the opening of plasma membrane Ca 2ϩ channels, a process known as capacitative calcium entry (1, 2). The signaling mechanism for the activation of capacitative calcium entry is not understood. A direct coupling model suggests that store depletion involves a functional coupling between (1,4,5)IP 3 receptors on the endoplasmic reticulum membrane and Ca 2ϩ entry channels on the plasma membrane (3, 4). Other models suggest that store depletion generates one or more second messengers which in turn activate Ca 2ϩ entry channels (5). Adenophostin A, a compound isolated from the culture broth of the Penicillium brevicompactum, is the most potent known agonist for the (1,4,5)IP 3 receptor. Its affinity for the (1,4,5)IP 3 receptor is about 100-fold greater than that of (1,4,5)IP 3 (6). Recently, two reports (7,8) . This suggests that in addition to its action as an agonist for the (1,4,5)IP 3 receptor, adenophostin A either acts downstream of (1,4,5)IP 3 in the pathway signaling capacitative calcium entry (perhaps on the channels themselves) or preferentially releases Ca 2ϩ from stores coupled to the activation of Ca 2ϩ entry. In this study, we have examined the effects of adenophostin A on Ca 2ϩ entry in a mammalian cell line, rat basophilic leukemia cells (RBL-1). Adenophostin A and (2,4,5)IP 3 , both non-metabolizable analogs of (1,4,5)IP 3 , were compared with regard to their abilities to release Ca 2ϩ from intracellular stores, to activate Ca 2ϩ entry, and to activate the well characterized calcium release-activated calcium current (I crac ) (9). While we find no evidence for a direct activation of calcium entry or of I crac by adenophostin A, we have discovered an unusual and unique ability of adenophostin A to support I crac under conditions of limited intracellular calcium buffering. Adenophostin A will be a useful tool for further investigations into the signaling mechanisms for capacitative calcium entry. EXPERIMENTAL PROCEDURESCell Culture and Materials-Rat basophilic leukemia cells (RBL-1, ATCC 1378-CRL, batch number F-13352) were cultured as recommended by ATCC. Adenophostin A was isolated as described previously (10). Ionomycin and 3-deoxy-3-fluoro-1,4,5-trisphosphate (3-F-IP 3 ) were...

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Rapid kinetic measurements of 45Ca2+ mobilization reveal that Ins(2,4,5)P3 is a partial agonist at hepatic InsP3 receptors

Cited by 38 publications

References 25 publications

Comparative Mechanistic and Substrate Specificity Study of Inositol Polyphosphate 5-Phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2

Comparative Mechanistic and Substrate Specificity Study of Inositol Polyphosphate 5-Phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2

Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle

Effect of Adenophostin A on Ca2+ Entry and Calcium Release-activated Calcium Current (I crac) in Rat Basophilic Leukemia Cells

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