scholarly journals Synthesis of dimeric analogs of adenophostin A that potently evoke Ca2+release through IP3receptors

RSC Advances ◽  
2016 ◽  
Vol 6 (89) ◽  
pp. 86346-86351 ◽  
Author(s):  
Amol M. Vibhute ◽  
Poornenth Pushpanandan ◽  
Maria Varghese ◽  
Vera Koniecnzy ◽  
Colin W. Taylor ◽  
...  
Keyword(s):  
Adenophostin A ◽  
Potent Agonist

Syntheses and Ca2+release potentials of four dimeric analogs of adenophostin A (AdA) through activation of type 1 IP3R are reported. These analogs are full agonists of IP3R and are equipotent to AdA, the most potent agonist of IP3R.

scholarly journals Ca2+ and calmodulin differentially modulate myo-inositol 1,4,5-trisphosphate (IP3)-binding to the recombinant ligand-binding domains of the various IP3 receptor isoforms

2000 ◽  
Vol 346 (2) ◽  
pp. 275-280 ◽  
Author(s):  
Sara VANLINGEN ◽  
Henk SIPMA ◽  
Patrick DE SMET ◽  
Geert CALLEWAERT ◽  
Ludwig MISSIAEN ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Recombinant Proteins ◽  
Ip3 Receptor ◽  
Binding Characteristics ◽  
Binding Domains ◽  
Receptor Isoforms ◽  
Inositol 1,4,5 Trisphosphate ◽  
Adenophostin A ◽  
Trisphosphate Receptor

We have expressed the N-terminal 581 amino acids of type 1 myo-inositol 1,4,5-trisphosphate receptor (IP3R1), IP3R2 and IP3R3 as recombinant proteins [ligand-binding site 1 (lbs-1), lbs-2, lbs-3] in the soluble fraction of Escherichia coli. These recombinant proteins contain the complete IP3-binding domain and bound IP3 and adenophostin A with high affinity. Ca2+ and calmodulin were previously found to maximally inhibit IP3 binding to lbs-1 by 42±6 and 43±6% respectively, and with an IC50 of approx. 200 nM and 3 μM respectively [Sipma, De Smet, Sienaert, Vanlingen, Missiaen, Parys and De Smedt (1999) J. Biol. Chem. 274, 12157-12562]. We now report that Ca2+ inhibited IP3 binding to lbs-3 with an IC50 of approx. 700 nM (37±4% inhibition at 5 μM Ca2+), while IP3 binding to lbs-2 was not affected by increasing [Ca2+] from 100 nM to 25 μM. Calmodulin (10 μM) inhibited IP3 binding to lbs-3 by 37±4%, while IP3 binding to lbs-2 was inhibited by only 11±2%. The inhibition of IP3 binding to lbs-3 by calmodulin was dose-dependent (IC50≈ 2 μM). We conclude that the IP3-binding domains of the various IP3R isoforms differ in binding characteristics for IP3 and adenophostin A, and are differentially modulated by Ca2+ and calmodulin, suggesting that the various IP3R isoforms can have different intracellular functions.

The role of tyrosine metabolism in the pathogenesis of chronic migraine

Cephalalgia ◽  
2013 ◽  
Vol 33 (11) ◽  
pp. 932-937 ◽  
Author(s):  
Giovanni D’Andrea ◽  
Domenico D’Amico ◽  
Gennaro Bussone ◽  
Andrea Bolner ◽  
Marco Aguggia ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Plasma Levels ◽  
High Plasma ◽  
Tension Type Headache ◽  
Predisposing Factor ◽  
Tyrosine Metabolism ◽  
Potent Agonist ◽  
Type Headache

Objective: The pathogenesis of chronic migraine (CM) remains largely unknown. We hypothesized that anomalies of tyrosine metabolism, found in migraine without aura (MwwA) patients, play an important role in the transformation of MwwA into CM, since the increase in the number of MwwA attacks is the most predisposing factor for the occurrence of CM. Methods: To test our hypothesis we measured the plasma levels of dopamine (DA), noradrenaline (NE) and trace amines, including tyramine (TYR) and octopamine (OCT), in a group of 73 patients with CM, 13 patients with chronic tension-type headache (CTTH) and 37 controls followed in the Headache Centers of the Neurology Departments of Asti, Milan and Vicenza hospitals in Italy. Results: The plasma levels of DA and NE were several-fold higher in CM patients compared with control subjects ( p > 0.001). The plasma levels of TYR were also extremely elevated ( p > 0.001); furthermore, these levels progressively increased with the duration of the CM. Conclusions: Our data support the hypothesis that altered tyrosine metabolism plays an important role in the pathogenesis of CM. The high plasma levels of TYR, a potent agonist of the trace amine associated receptors type 1 (TAAR1), may ultimately down-regulate this receptor because of loss of inhibitory presynaptic regulation, therein resulting in uncontrolled neurotransmitter release. This may produce functional metabolic consequences in the synaptic clefts of the pain matrix implicated in CM.

scholarly journals Selective determinants of inositol 1,4,5-trisphosphate and adenophostin A interactions with type 1 inositol 1,4,5-trisphosphate receptors

2010 ◽  
Vol 161 (5) ◽  
pp. 1070-1085 ◽  
Author(s):  
Ana M Rossi ◽  
Kana M Sureshan ◽  
Andrew M Riley ◽  
Barry VL Potter ◽  
Colin W Taylor
Keyword(s):  
Inositol 1,4,5 Trisphosphate ◽  
Adenophostin A

scholarly journals Determinants of adenophostin A binding to inositol trisphosphate receptors

2002 ◽  
Vol 367 (1) ◽  
pp. 113-120 ◽  
Author(s):  
Stephen A. MORRIS ◽  
Edmund P. NEROU ◽  
Andrew M. RILEY ◽  
Barry V.L. POTTER ◽  
Colin W. TAYLOR
Keyword(s):  
Binding Domain ◽  
Sf9 Cells ◽  
Receptor Subtypes ◽  
Ip3 Receptors ◽  
Ip3 Receptor ◽  
High Affinity ◽  
Recombinant Type ◽  
Adenophostin A ◽  
Binding Core

Inositol 1,4,5-trisphosphate (IP3) receptors from cerebellum and recombinant type 1 IP3 receptors expressed in Sf9 cells had indistinguishable affinities for IP3 (Kd = 6.40±0.48nM) and adenophostin A (Kd = 0.89±0.05nM). In cytosol-like medium, each of the three mammalian IP3 receptor subtypes when expressed in Sf9 cells bound adenophostin A with greater affinity than IP3. It has been suggested that adenophostin A binds with high affinity only in the presence of ATP, but we found that adenophostin A similarly displaced [3H]IP3 from type 1 IP3 receptors whatever the ATP concentration. N-terminal fragments of the type 1 receptor were expressed with and without the S1 splice site; its removal had no effect on [3H]IP3 binding to the 1—604 protein, but abolished binding to the 224—604 protein. The 1—604 fragment and full-length receptor bound adenophostin A with the same affinity, but the fragment had 3-fold greater affinity for IP3, suggesting that C-terminal residues selectively inhibit IP3 binding. The 224—604S1+ fragment bound IP3 and adenophostin A with increased affinity, but as with the 1—604 fragment it bound adenophostin A with only 2-fold greater affinity than IP3. High-affinity binding of adenophostin A may be partially determined by its 2′-phosphate interacting more effectively than the 1-phosphate of IP3 with residues within the IP3-binding core. This may account for the 2-fold greater affinity of adenophostin A relative to IP3 for the minimal IP3-binding domain. In addition we suggest that C-terminal residues, which impede access of IP3, may selectively interact with adenophostin A to allow it unhindered access to the IP3-binding domain.

scholarly journals Ca2+-calmodulin inhibits Ca2+ release mediated by type-1, -2 and -3 inositol trisphosphate receptors

2000 ◽  
Vol 345 (2) ◽  
pp. 357-363 ◽  
Author(s):  
Charles E. ADKINS ◽  
Stephen A. MORRIS ◽  
Humbert DE SMEDT ◽  
Ilse SIENAERT ◽  
Katalin TÖRÖK ◽  
...  
Keyword(s):  
Calcineurin Inhibitors ◽  
Cell Types ◽  
Receptor Subtypes ◽  
Glutathione S Transferase ◽  
Calmodulin Binding ◽  
Insp3 Receptors ◽  
Adenophostin A ◽  
A Site ◽  
Insp3 Receptor

InsP3 binding to type-1, but not type-3, InsP3 receptors is inhibited by calmodulin in a Ca2+-independent fashion [Cardy and Taylor (1998) Biochem. J. 334, 447-455], and Ca2+ mobilization by type-1 InsP3 receptors of cerebellum is inhibited by calmodulin [Patel, Morris, Adkins, O'Beirne and Taylor (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 11627-11632]. Using cell types expressing predominantly type-1, -2 or -3 InsP3 receptors, we show that InsP3-evoked Ca2+ mobilization from each is similarly inhibited by calmodulin. In SH-SY5Y cells, which express largely type-1 receptors, calmodulin (IC50 ≈ 15 μM) inhibited InsP3-evoked Ca2+ release only in the presence of Ca2+. The inhibition was unaffected by calcineurin inhibitors. The effect of calmodulin did not result from enhanced metabolism of InsP3 because calmodulin also decreased the sensitivity of the Ca2+ stores to adenophostin A, a non-metabolizable InsP3-receptor agonist. Protein kinase A-catalysed phosphorylation of type-1 InsP3 receptors was unaffected by Ca2+-calmodulin. Using a scintillation proximity assay to measure 125I-calmodulin binding to glutathione S-transferase-fusion proteins, we identified two regions of the type-1 InsP3 receptor (cyt1, residues -6 to 159; and cyt11, residues 1499-1649) that bound 125I-calmodulin. The higher-affinity site (cyt11) was also photoaffinity labelled with N-hydroxysuccinimidyl-4-azidobenzoate (HSAB)-calmodulin. We speculate that Ca2+-independent binding of calmodulin to a site within the first 159 residues of the type-1 InsP3 receptor inhibits InsP3 binding and may thereby regulate the kinetics of Ca2+ release. Ca2+-dependent inhibition of Ca2+ release by calmodulin is mediated by a different site: it may reside on an accessory protein that associates with all three receptor subtypes, or Ca2+-calmodulin binding to a site lying between residues 1499 and 1649 of the type-1 receptor may inhibit Ca2+ release from any tetrameric receptor that includes a type-1 subunit.

Crystalloid Inclusions in Hepatocyte Mitochondria and Their Similarity to Cytoplasmic Crystalloids

1974 ◽  
Vol 32 ◽  
pp. 198-199
Author(s):  
Odell T. Minick ◽  
Hidejiro Yokoo
Keyword(s):  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Special Interest ◽  
Structural Variations ◽  
Mitochondrial Alterations ◽  
The Matrix ◽  
Crystalloid Inclusions ◽  
Liver Biopsies

Mitochondrial alterations were studied in 25 liver biopsies from patients with alcoholic liver disease. Of special interest were the morphologic resemblance of certain fine structural variations in mitochondria and crystalloid inclusions. Four types of alterations within mitochondria were found that seemed to relate to cytoplasmic crystalloids.Type 1 alteration consisted of localized groups of cristae, usually oriented in the long direction of the organelle (Fig. 1A). In this plane they appeared serrated at the periphery with blind endings in the matrix. Other sections revealed a system of equally-spaced diagonal lines lengthwise in the mitochondrion with cristae protruding from both ends (Fig. 1B). Profiles of this inclusion were not unlike tangential cuts of a crystalloid structure frequently seen in enlarged mitochondria described below.

Evidence for a shear mechanism for the precipitation of γ-zirconium hydride in zirconium

1978 ◽  
Vol 36 (1) ◽  
pp. 658-659
Author(s):  
G.J.C. Carpenter
Keyword(s):  
Elevated Temperature ◽  
Strain Field ◽  
Zirconium Hydride ◽  
Zirconium Atom ◽  
Atom Diffusion ◽  
Solvus Temperature ◽  
Hexagonal Close Packed ◽  
Partial Dislocations ◽  
The Face

In zirconium-hydrogen alloys, rapid cooling from an elevated temperature causes precipitation of the face-centred tetragonal (fct) phase, γZrH, in the form of needles, parallel to the close-packed <1120>zr directions (1). With low hydrogen concentrations, the hydride solvus is sufficiently low that zirconium atom diffusion cannot occur. For example, with 6 μg/g hydrogen, the solvus temperature is approximately 370 K (2), at which only the hydrogen diffuses readily. Shears are therefore necessary to produce the crystallographic transformation from hexagonal close-packed (hep) zirconium to fct hydride.The simplest mechanism for the transformation is the passage of Shockley partial dislocations having Burgers vectors (b) of the type 1/3<0110> on every second (0001)Zr plane. If the partial dislocations are in the form of loops with the same b, the crosssection of a hydride precipitate will be as shown in fig.1. A consequence of this type of transformation is that a cumulative shear, S, is produced that leads to a strain field in the surrounding zirconium matrix, as illustrated in fig.2a.

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