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Hon Cheung Lee - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for enzymatic evolution from a dedicated ADP Ribosyl Cyclase to a multifunctional nad hydrolase
    Journal of Biological Chemistry, 2009
    Co-Authors: Qun Liu, Hon Cheung Lee, Irina A Kriksunov, Richard M Graeff, Barry V L Potter, Hong Jiang, Bo Zhang, Norman J Oppenheimer, Hening Lin
    Abstract:

    Cyclic ADP-ribose (cADPR) is a universal calcium messenger molecule that regulates many physiological processes. The production and degradation of cADPR are catalyzed by a family of related enzymes, including the ADP-Ribosyl Cyclase from Aplysia california (ADPRAC) and CD38 from human. Although ADPRC and CD38 share a common evolutionary ancestor, their enzymatic functions toward NAD and cADPR homeostasis have evolved divergently. Thus, ADPRC can only generate cADPR from NAD (Cyclase), whereas CD38, in contrast, has multiple activities, i.e. in cADPR production and degradation, as well as NAD hydrolysis (NADase). In this study, we determined a number of ADPRC and CD38 structures bound with various nucleotides. From these complexes, we elucidated the structural features required for the cyclization (Cyclase) reaction of ADPRC and the NADase reaction of CD38. Using the structural approach in combination with site-directed mutagenesis, we identified Phe-174 in ADPRC as a critical residue in directing the folding of the substrate during the cyclization reaction. Thus, a point mutation of Phe-174 to glycine can turn ADPRC from a Cyclase toward an NADase. The equivalent residue in CD38, Thr-221, is shown to disfavor the cyclizing folding of the substrate, resulting in NADase being the dominant activity. The comprehensive structural comparison of CD38 and APDRC presented in this study thus provides insights into the structural determinants for the functional evolution from a Cyclase to a hydrolase.

  • Mechanism of cyclizing NAD to cyclic ADP-ribose by ADP-Ribosyl Cyclase and CD38
    Journal of Biological Chemistry, 2009
    Co-Authors: Richard Graeff, Quan Hao, Masayo Kotaka, Norman Oppenheimer, Irina A Kriksunov, Qun Liu, Hon Cheung Lee
    Abstract:

    Mammalian CD38 and its Aplysia homolog, ADP-Ribosyl Cyclase (Cyclase), are two prominent enzymes that catalyze the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a Ca(2+) messenger molecule responsible for regulating a wide range of cellular functions. Although both use NAD as a substrate, the Cyclase produces cADPR, whereas CD38 produces mainly ADP-ribose (ADPR). To elucidate the catalytic differences and the mechanism of cyclizing NAD, the crystal structure of a stable complex of the Cyclase with an NAD analog, Ribosyl-2'F-2'deoxynicotinamide adenine dinucleotide (ribo-2'-F-NAD), was determined. The results show that the analog was a substrate of the Cyclase and that during the reaction, the nicotinamide group was released and a stable intermediate was formed. The terminal Ribosyl unit at one end of the intermediate formed a close linkage with the catalytic residue (Glu-179), whereas the adenine ring at the other end stacked closely with Phe-174, suggesting that the latter residue is likely to be responsible for folding the linear substrate so that the two ends can be cyclized. Mutating Phe-174 indeed reduced cADPR production but enhanced ADPR production, converting the Cyclase to be more CD38-like. Changing the equivalent residue in CD38, Thr-221 to Phe, correspondingly enhanced cADPR production, and the double mutation, Thr-221 to Phe and Glu-146 to Ala, effectively converted CD38 to a Cyclase. This study provides the first detailed evidence of the cyclization process and demonstrates the feasibility of engineering the reactivity of the enzymes by mutation, setting the stage for the development of tools to manipulate cADPR metabolism in vivo.

  • Regulation of nuclear Ca2+ signaling by translocation of the Ca2+ messenger synthesizing enzyme ADP-Ribosyl Cyclase during neuronal depolarization.
    Journal of Biological Chemistry, 2008
    Co-Authors: Stéphanie Bezin, Hon Cheung Lee, Gilles Charpentier, Gérard Baux, Philippe Fossier, José-manuel Cancela
    Abstract:

    In neurons, voltage-gated Ca(2+) channels and nuclear Ca(2+) signaling play important roles, such as in the regulation of gene expression. However, the link between electrical activity and biochemical cascade activation involved in the generation of the nuclear Ca(2+) signaling is poorly understood. Here we show that depolarization of Aplysia neurons induces the translocation of ADP-Ribosyl Cyclase, a Ca(2+) messenger synthesizing enzyme, from the cytosol into the nucleus. The translocation is dependent on Ca(2+) influx mainly through the voltage-dependent L-type Ca(2+) channels. We report also that specific nucleoplasmic Ca(2+) signals can be induced by three different calcium messengers, cyclic ADP-ribose, nicotinic acid adenine dinucleotide phosphate (NAADP), both produced by the ADP-Ribosyl Cyclase, and inositol 1,4,5-trisphosphate (IP(3)). Moreover, our pharmacological data show that NAADP acts on its own receptor, which cooperates with the IP(3) and the ryanodine receptors to generate nucleoplasmic Ca(2+) oscillations. We propose a new model where voltage-dependent L-type Ca(2+) channel-induced nuclear translocation of the cytosolic Cyclase is a crucial step in the fine tuning of nuclear Ca(2+) signals in neurons.

  • Hierarchical and helical self-assembly of ADP-Ribosyl Cyclase into large-scale protein microtubes
    Journal of Physical Chemistry B, 2008
    Co-Authors: Qun Liu, Richard Graeff, Hon Cheung Lee, Irina A Kriksunov, Zhongwu Wang, Quan Hao
    Abstract:

    Proteins are macromolecules with characteristic structures and biological functions. It is extremely challenging to obtain protein microtube structures through self-assembly as proteins are very complex and flexible. Here we present a strategy showing how a specific protein, ADP-Ribosyl Cyclase, helically self-assembles from monomers into hexagonal nanochains and further to highly ordered crystalline microtubes. The structures of protein nanochains and consequently self-assembled superlattice were determined by X-ray crystallography at 4.5 A resolution and imaged by scanning electron microscopy. The protein initially forms into dimers that have a fixed size of 5.6 nm, and then, helically self-assembles into 35.6 nm long hexagonal nanochains. One such nanochain consists of six dimers (12 monomers) that stack in order by a pseudo P6(1) screw axis. Seven nanochains produce a series of large-scale assemblies, nanorods, forming the building blocks for microrods. A proposed aging process of microrods results in the formation of hollow microstructures. Synthesis and characterization of large scale self-assembled protein microtubes may pave a new pathway, capable of not only understanding the self-assembly dynamics of biological materials, but also directing design and fabrication of multifunctional nanobuilding blocks with particular applications in biomedical engineering.

  • ADP Ribosyl Cyclase crystal structures reveal a covalent intermediate
    Structure, 2004
    Co-Authors: Michael L Love, Hon Cheung Lee, Irina A Kriksunov, Richard M Graeff, Cyrus Munshi, Daniel J Thiel, Doletha M E Szebenyi, Quan Hao
    Abstract:

    Abstract ADP-Ribosyl Cyclase catalyzes the elimination of nicotinamide from NAD and cyclization to cADPR, a known second messenger in cellular calcium signaling pathways. We have determined to 2.0 A resolution the structure of Aplysia Cyclase with ribose-5-phosphate bound covalently at C3′ and with the base exchange substrate (BES), pyridylcarbinol, bound to the active site. In addition, further refinement at 2.4 A resolution of the structure of nicotinamide-bound Cyclase, which was previously reported, reveals that ribose-5-phosphate is also covalently bound in this structure, and a second nicotinamide site was identified. The structures of native and mutant Glu179Ala Cyclase were also solved to 1.7 and 2.0 A respectively. It is proposed that the second nicotinamide site serves to promote cyclization by clearing the active site of the nicotinamide byproduct. Moreover, a Ribosylation mechanism can be proposed in which the cyclization reaction proceeds through a covalently bound intermediate.

Haruhiro Higashida - One of the best experts on this subject based on the ideXlab platform.

  • oxytocin induced elevation of ADP Ribosyl Cyclase activity cyclic ADP riboseor ca2 concentrations is involved in autoregulation of oxytocin secretionin the hypothalamus and posterior pituitary in male mice
    Neuropharmacology, 2010
    Co-Authors: Olga Lopatina, Minako Hashii, Hongxiang Liu, Sarwat Amina, Haruhiro Higashida
    Abstract:

    Locally released oxytocin (OT) activates OT receptors (2.1:OXY:1:OT:) in neighboring neurons in the hypothalamus and their terminals in the posterior pituitary, resulting in further OT release, best known in autoregulation occurring during labor or milk ejection in reproductive females. OT also plays a critical role in social behavior of non-reproductive females and even in males in mammals from rodents to humans. Social behavior is disrupted when elevation of free intracellular Ca(2+) concentration ([Ca(2+)](i)) and OT secretion are reduced in male and female CD38 knockout mice. Therefore, it is interesting to investigate whether ADP-Ribosyl Cyclase-dependent signaling is involved in OT-induced OT release for social recognition in males, independent from female reproduction, and to determine its molecular mechanism. Here, we report that ADP-Ribosyl Cyclase activity was increased by OT in crude membrane preparations of the hypothalamus and posterior pituitary in male mice, and that OT elicited an increase in [Ca(2+)](i) in the isolated terminals over a period of 5 min. The increases in Cyclase and [Ca(2+)](i) were partially inhibited by nonspecific protein kinase inhibitors and a protein kinase C specific inhibitor, calphostin C. Subsequently, OT-induced OT release was also inhibited by calphostin C to levels inhibited by vasotocin, an OT receptor antagonist, and 8-bromo-cADP-ribose. These results demonstrate that OT receptors are functionally coupled to membrane-bound ADP-Ribosyl Cyclase and/or CD38 and suggest that cADPR-mediated intracellular calcium signaling is involved in autoregulation of OT release, which is sensitive to protein kinase C, in the hypothalamus and neurohypophysis in male mice.

  • bradykinin activates ADP Ribosyl Cyclase in neuroblastoma cells intracellular concentration decrease in nad and increase in cyclic ADP ribose
    FEBS Letters, 2006
    Co-Authors: Haruhiro Higashida, A B Salmina, Mami Noda, Shigeru Yokoyama, Minako Hashii, Jia Sheng Zhang, Zen Guo Zhong, Duo Jin
    Abstract:

    ADP-Ribosyl Cyclase activity in the crude membrane fraction of neuroblastomaxglioma NGPM1-27 hybrid cells was measured by monitoring [(3)H] cyclic ADP-ribose (cADPR) formation from [(3)H] NAD(+). Bradykinin (BK) at 100nM increased ADP-Ribosyl Cyclase activity by about 2.5-fold. Application of 300nM BK to living NGPM1-27 cells decreased NAD(+) to 78% of the prestimulation level at 30s. In contrast, intracellular cADPR concentrations were increased by 2-3-fold during the period from 30 to 120s after the same treatment. Our results suggest that cADPR is one of the second messengers downstream of B(2) BK receptors.

  • ADP Ribosyl Cyclase as a therapeutic target for central nervous system diseases
    Central nervous system agents in medicinal chemistry, 2006
    Co-Authors: A B Salmina, Raissa Ya Olovyannikova, Mami Noda, Haruhiro Higashida
    Abstract:

    NAD+ is as abundant as ATP in neuronal cells. NAD+ functions not only as a coenzyme but also as a substrate. NAD+ metabolism in neuronal cells is tightly controlled under physiological conditions, since NAD+ has a great impact on functional activity of neurons upon stimulation. NAD+-utilizing enzymes is involved in signal transduction. We focus on ADP-Ribosyl Cyclase/CD38 which synthesizes cyclic ADP-ribose (cADPR), a Ca2+ mobilizing messenger. Structural analysis defined the active site of the enzyme. ADP-Ribosyl Cyclase associated with CD38 was detected in the central nervous system (CNS) where its activity and expression were developmentally regulated. CD38 has been reported to have different subcellular locations either in neurons or in glial cells, suggesting multiple roles. cADPR, acts as a universal calcium mobilizer from intracellular stores independently from inositol trisphosphate which acts through activation/ modulation of ryanodine receptor channels involving FKBP12.6. cADPR was also involved in the regulation of some potassium currents in synaptic activity. cADPR synthesis in neuronal cells is stimulated or modulated via different pathways and various factors. Subtype-specific coupling of various neurotransmitter receptors with ADP-Ribosyl Cyclase confirms the involvement of the enzyme in signal transduction in neurons and glial cells. Therefore, it is possible that pharmacological manipulation of intracellular cADPR levels through ADP-Ribosyl Cyclase activity or expression, in the CNS may provide new therapeutic opportunities for treatment of neurological disorders.

  • subtype specific coupling with ADP Ribosyl Cyclase of metabotropic glutamate receptors in retina cervical superior ganglion and ng108 15 cells
    Journal of Neurochemistry, 2003
    Co-Authors: Haruhiro Higashida, Mami Noda, Minako Hashii, Jia Sheng Zhang, Sumiko Mochida, Xiao Liang Chen, Yeonsook Shin, Kazi Zakir Hossain, Naoto Hoshi, Ryuichi Shigemoto
    Abstract:

    Cyclic ADP-ribose (cADP-ribose) is a putative second messenger or modulator. However, the role of cADP-ribose in the downstream signals of the metabotropic glutamate receptors (mGluRs) is unclear. Here, we show that glutamate stimulates ADP-Ribosyl Cyclase activity in rat or mouse crude membranes of retina via group III mGluRs or in superior cervical ganglion via group I mGluRs. The retina of mGluR6-deficient mice showed no increase in the ADP-Ribosyl Cyclase level in response to glutamate. GTP enhanced the initial rate of basal and glutamate-stimulated Cyclase activity. GTP-γ-S also stimulated basal activity. To determine whether the coupling mode of mGluRs to ADP-Ribosyl Cyclase is a feature common to individual cloned mGluRs, we expressed each mGluR subtype in NG108-15 neuroblastoma × glioma hybrid cells. The glutamate-induced stimulation of the Cyclase occurs preferentially in NG108-15 cells over-expressing mGluRs1, 3, 5, and 6. Cells expressing mGluR2 or mGluRs4 and 7 exhibit inhibition or no coupling, respectively. Glutamate-induced activation or inhibition of the Cyclase activity was eliminated after pre-treatment with cholera or pertussis toxin, respectively. Thus, the subtype-specific coupling of mGluRs to ADP-Ribosyl Cyclase via G proteins suggests that some glutamate-evoked neuronal functions are mediated by cADP-ribose.

  • membrane bound form of ADP Ribosyl Cyclase in rat cortical astrocytes in culture
    Journal of Neurochemistry, 2001
    Co-Authors: Taeko Hotta, Kiyofumi Asai, Kaori Fujita, Taiji Kato, Haruhiro Higashida
    Abstract:

    ADP-Ribosyl Cyclase activities in cultured rat astrocytes were examined by using TLC for separation of enzymatic products. A relatively high rate of [3H]cyclic ADP-ribose production converted from [3H]NAD+ by ADP-Ribosyl Cyclase (2.015+/-0.554 nmol/min/mg of protein) was detected in the crude membrane fraction of astrocytes, which contained approximately 50% of the total Cyclase activity in astrocytes. The formation rate of [3H]ADP-ribose from cyclic ADP-ribose by cyclic ADP-ribose hydrolase and/or from NAD+ by NAD glycohydrolase was low and enriched in the cytosolic fraction. Although NAD+ in the extracellular medium was metabolized to cyclic ADP-ribose by incubating cultures of intact astrocytes, the presence of Triton X-100 in the medium for permeabilizing cells increased cyclic ADP-ribose production three times as much. Isoproterenol and GTP increased [3H]cyclic ADP-ribose formation in crude membrane-associated Cyclase activity. This isoproterenol-induced stimulation of membrane-associated ADP-Ribosyl Cyclase activity was confirmed by cyclic GDP-ribose formation fluorometrically. This stimulatory action was blocked by prior treatment of cells with cholera toxin but not with pertussis toxin. These results suggest that ADP-Ribosyl Cyclase in astrocytes has both extracellular and intracellular actions and that signals of beta-adrenergic stimulation are transduced to membrane-bound ADP-Ribosyl Cyclase via G proteins within cell surface membranes of astrocytes.

Toshiaki Katada - One of the best experts on this subject based on the ideXlab platform.

  • oscillation of ADP Ribosyl Cyclase activity during the cell cycle and function of cyclic ADP ribose in a unicellular organism euglena gracilis
    FEBS Letters, 1997
    Co-Authors: Wataru Masuda, Hiroshi Nishina, Kiyoshi Inageda, Katsunobu Takahashi, Toshiaki Katada, Shigeo Takenaka, Shingo Tsuyama, Hiroshi Inui, Kazutaka Miyatake, Yoshihisa Nakano
    Abstract:

    Abstract In Euglena gracilis , the activity of ADP-Ribosyl Cyclase, which produces cyclic ADP-ribose, oscillated during the cell cycle in a synchronous culture induced by a light-dark cycle, and a marked increase in the activity was observed in the G2 phase. Similarly, the ADP-Ribosyl Cyclase activity rose extremely immediately before cell division started, when synchronous cell division was induced by adding cobalamin (which is an essential growth factor and participates in DNA synthesis in this organism) to its deficient culture. Further, cADPR in these cells showed a maximum level immediately before cell division started. A dose-dependent Ca 2+ release was observed when microsomes were incubated with cADPR. © 1997 Federation of European Biochemical Societies.

  • stimulation of ADP Ribosyl Cyclase activity of the cell surface antigen cd38 by zinc ions resulting from inhibition of its nad glycohydrolase activity
    FEBS Journal, 1996
    Co-Authors: Iwao Kukimoto, Hiroshi Nishina, Kiyoshi Inageda, Katsunobu Takahashi, Shinichi Hoshino, Kenji Kontani, Toshiaki Katada
    Abstract:

    The lymphocyte cell surface antigen, CD38, which has an amino acid sequence similar to Aplysia ADP-Ribosyl Cyclase, catalyzes not only the hydrolysis of NAD+ and 1-(5-phospho-beta-D-Ribosyl) adenosine 5'-phosphate cyclic anhydride (cyclic ADP-ribose) but also the formation of cyclic ADP-ribose from NAD+. To characterize the bifunctional enzyme properties, we produced the recombinant CD38 fused with a maltose-binding protein (MBP-CD38). Zinc ions stimulated the ADP-Ribosyl Cyclase activity of MBP-CD38, but inversely inhibited its NAD+ glycohydrolase activity which was approximately 100-fold dominant to the Cyclase activity in the absence of Zn2+. Such dual effects of Zn2+ were also observed in the native membrane-bound CD38 of HL-60 cells which had been caused to differentiate by retinoic acid. Zinc ions inhibited the NAD+ glycohydrolase reaction catalyzed by MBP-CD38 in an uncompetitive manner, whereas they enhanced the ADP-Ribosyl Cyclase reaction without affecting the Km value for NAD+. There was an increase in the fluorescence intensity of a hydrophobic fluorescent probe, 8-anilino-1-naphthalenesulfonate, in the presence of MBP-CD38. The fluorescence increase was further enhanced by the addition of Zn2+ with a shift in the maximum emission wavelength from 484 nm to 470 nm, suggesting that Zn2+ caused conformational changes of MBP-CD38. These results indicate that Zn2+ directly interacts with CD38 to stimulate its ADP-Ribosyl Cyclase with inhibition of its NAD+ glycohydrolase, probably due to prevention of the access of water molecule to an intermediate of the enzymesubstrate complex.

  • inhibition of nad glycohydrolase and ADP Ribosyl Cyclase activities of leukocyte cell surface antigen cd38 by gangliosides
    Journal of Biological Chemistry, 1996
    Co-Authors: Miki Harayokoyama, Hiroshi Nishina, Iwao Kukimoto, Kenji Kontani, Yoshio Hirabayashi, Fumitoshi Irie, Hiroshi Sugiya, Shunsuke Furuyama, Toshiaki Katada
    Abstract:

    We have recently reported that gangliosides act as inhibitors of ADP-Ribosyltransferases and NAD+ glycohydrolases (NADase) of pertussis toxin and the C3 exoenzyme from Clostridium botulinum (Hara-Yokoyama, M., Hirabayashi, Y., Irie, F., Syuto, B., Moriishi, K., Sugiya, H., and Furuyama, S. (1995) J. Biol. Chem. 270, 8115-8121). Here, we investigated the effect of gangliosides on the enzymatic activity of leukocyte cell surface antigen CD38, which is identified as an ecto-NADase (Kontani, K., Nishina, H., Ohoka, Y., Takahashi, K., and Katada, T. (1993) J. Biol. Chem. 268, 16895-16898). Gangliosides GM1a and GQ1balpha inhibited the NADase activity in the immunoprecipitate of anti-CD38 antibody from the membrane extract of retinoic acid-treated human leukemic HL-60 cells. Gangliosides also inhibited the NADase activity of the extracellular domain of CD38 antigen that was deprived of the transmembrane domain and was expressed in Escherichia coli as a fusion protein with maltose-binding protein (MBP-CD38). The order of the inhibitory effect of purified ganglioside species on the NADase activity on MBP-CD38 was as follows: GQ1balpha > GT1b, GQ1b > GD1a, GD1b, GM1a, GM1b, GD3, GM3. GQ1balpha inhibited the NADase of MBP-CD38 in a noncompetitive manner versus NAD+ with a Ki value of about 0.3 microM. Neither ceramide nor the oligosaccharide moiety of GQ1balpha had an effect on the NADase activity. GQ1balpha, GT1b, and GQ1b also efficiently inhibited the ADP-Ribosyl Cyclase activity of MBP-CD38. At present, gangliosides are the only endogenous species that can block the enzymatic activity of CD38 antigen. The present results suggest a potential role of gangliosides as inhibitors of the ecto-NADases.

  • enzyme properties of aplysia ADP Ribosyl Cyclase comparison with nad glycohydrolase of cd38 antigen
    Journal of Biochemistry, 1995
    Co-Authors: Kiyoshi Inageda, Hiroshi Nishina, Katsunobu Takahashi, Shinichi Hoshino, Kenichi Tokita, Yasunori Kanaho, Iwao Kukimoto, Kenji Kontani, Toshiaki Katada
    Abstract:

    An ecto-enzyme of NAD glycohydrolase (NADase) induced by retinoic acid in HL-60 cells is attributed to the molecule of CD38 antigen [Kontani, K., Nishina, H., Ohoka, Y., Takahashi, K., and Katada, T. (1993) J. Biol. Chem. 268, 16895-16898]. CD38 antigen has an amino acid sequence homologous to Aplysia ADP-Ribosyl Cyclase which generates cyclic adenosine diphosphoribose (cADPR) and nicotinamide (NA) from beta-NAD+. On the basis of this sequence homology, we compared enzyme properties between CD38 NADase expressed as a fusion protein in Escherichia coli and ADP-Ribosyl Cyclase purified from the ovotestis of Aplysia kurodai. 1) beta-NAD+ analogs, nicotinamide 1, N6-ethenoadenine dinucleotide, and nicotinamide hypoxanthine dinucleotide, did not serve as good substrates for the ADP-Ribosyl Cyclase, suggesting that the intact adenine ring of beta-NAD+ was required for the Cyclase-catalyzed reaction. On the other hand, CD38 NADase utilized the NAD analogs to form ADP-ribose and NA. 2) Kinetic analyses of the ADP-Ribosyl Cyclase reaction revealed that NA was first released from the substrate (beta-NAD+)-enzyme complex, followed by the release of another product, cADPR, which was capable of interacting with the free enzyme. 3) The enzyme reaction catalyzed by the ADP-Ribosyl Cyclase was fully reversible; beta-NAD+ could be formed from cADPR and NA with a velocity similar to that observed in the degradation of beta-NAD+. However, CD38 NADase did not catalyze the reverse reaction to form beta-NAD+ from ADP-ribopase and NA. 4) The CD38 NADase activity was, but the ADP-Ribosyl Cyclase activity was not, inhibited by dithiothreitol.(ABSTRACT TRUNCATED AT 250 WORDS)

  • cell surface antigen cd38 identified as ecto enzyme of nad glycohydrolase has hyaluronate binding activity
    Biochemical and Biophysical Research Communications, 1994
    Co-Authors: Hiroshi Nishina, Kiyoshi Inageda, Katsunobu Takahashi, Shinichi Hoshino, K Ikeda, Toshiaki Katada
    Abstract:

    Abstract An ecto-enzyme of NAD glycohydrolase induced by retinoic acid in human leukemic HL-60 cells is attributed to the molecule of leukocyte cell surface antigen CD38 (Kontani, K., et al. (1993) J. Biol. Chem. 268, 16895-16898). The cell surface antigen has an amino acid sequence homologous to Aplysia ADP-Ribosyl Cyclase that catalyzes the conversion of NAD to cyclic ADP-ribose with a calcium-mobilizing activity. A putative hyaluronate (HA)-binding motif which has recently been identified in CD44 antigen existed in the extracellular domain and intracellular amino terminus of CD38 antigen, CD38 antigen was indeed capable of binding to HA in a manner dependent on ionic strength. By contrast, no binding activity was found in Aplysia ADP-Ribosyl Cyclase. Thus CD38 antigen, like CD43 antigen characterized as a HA-receptor (or binding) protein, may function as an adhesion molecule.

Uhhyun Kim - One of the best experts on this subject based on the ideXlab platform.

  • Running Title: ADP-Ribosyl Cyclase and Cardiac Hypertrophy
    2013
    Co-Authors: Rukhsana Gul A, Seon-young Kim A, Kwang-hyun Park A, Byung-ju Kim A, Se-jin Kim A, Mie-jae Im A A, Uhhyun Kim
    Abstract:

    ADP Ribosyl-Cyclase (ADPR-Cyclase) produces a Ca 2+ mobilizing second messenger, cyclic ADP-ribose (cADPR), from NAD +. In this study, we investigated molecular basis of ADPR-Cyclase activation in Angiotensin II (Ang II) signaling pathway and cellular responses in adult rat cardiomyocytes. The results showed that Ang II generated a biphasic [Ca 2+]i increases that include a rapid transient Ca 2+ elevation via IP3 receptor, and sustained Ca 2+ rise via the activation of L-type Ca 2+ channel and opening of ryanodine receptor (RyR). Ang II-induced sustained Ca 2+ rise was blocked by a cADPR antagonistic analog, 8-Bromo-cADPR, indicating that sustained Ca 2+ rise is mediated by cADPR. Supporting the notion, ADPR-Cyclase activity and cADPR production by Ang II were increased in a time-dependent manner. Application of pharmacological inhibitors and immunologic analyses revealed that cADPR formation was activated by sequential activation of Src, phosphatidylinositol-3-kinase (PI3K)/Akt, phospholipase C (PLC)-

  • inhibition of ADP Ribosyl Cyclase attenuates angiotensin ii induced cardiac hypertrophy
    Cardiovascular Research, 2009
    Co-Authors: Rukhsana Gul, Seonyoung Kim, Jaehyeong Park, Kyu Yoon Jang, Jeikeon Chae, Uhhyun Kim
    Abstract:

    Aims Here, we report the discovery of a small molecule inhibitor, 2,2′-dihydroxyazobenzene (DAB), of ADP Ribosyl Cyclase (ADPR-Cyclase) and showed that this inhibitor attenuated angiotensin (Ang) II-induced hypertrophic responses. Methods and results The intracellular concentration of free Ca2+ [Ca2+]i in adult rat cardiomyocytes was measured by using a confocal microscope. Cardiac hypertrophy was induced by the two-kidney one-clip (2K1C) method. Hypertrophy was determined by de novo protein synthesis, cell volume, echocardiography, nuclear translocation of nuclear factor of activated T-cells, and transforming growth factor-β1 protein expression. Treatment of cardiomyocytes with Ang II generated a biphasic [Ca2+]i increase that included an initial Ca2+peak and sustained Ca2+ rise via inositol trisphosphate and cyclic ADP-ribose (cADPR) formation, respectively. A cADPR antagonistic analogue, 8-Br-cADPR, and an ADPR-Cyclase inhibitor, DAB, blocked the sustained Ca2+ signal, but not the initial Ca2+ rise. Furthermore, DAB significantly inhibited Ang II-mediated cADPR formation and hypertrophic responses in vitro . Echocardiography and histological examination revealed significant cardiac hypertrophy in 2K1C rats that was potently inhibited by treatment with DAB. In addition, the hypertrophic responses induced by Ang II in vitro were significantly increased by 2K1C, and DAB treatment reversed these hypertrophic responses to the levels of sham Control. Conclusion ADPR-Cyclase is an important mediator of cardiac hypertrophy, and inhibition of ADPR-Cyclase by DAB may provide a new therapeutic strategy for cardiac diseases.

  • role of kidney ADP Ribosyl Cyclase in diabetic nephropathy
    American Journal of Physiology-renal Physiology, 2009
    Co-Authors: Seonyoung Kim, Rukhsana Gul, Kwanghyun Park, Kyu Yoon Jang, Uhhyun Kim
    Abstract:

    The role of ADP-Ribosyl Cyclases (ADPR-Cyclases) in diabetic nephropathy was investigated. ADPR-Cyclases synthesize cADP-ribose (cADPR), a Ca2+-mobilizing second messenger, and are stimulated by G ...

  • a novel signaling pathway of ADP Ribosyl Cyclase activation by angiotensin ii in adult rat cardiomyocytes
    American Journal of Physiology-heart and Circulatory Physiology, 2008
    Co-Authors: Rukhsana Gul, Seonyoung Kim, Kwanghyun Park, Byungju Kim, Sejin Kim, Uhhyun Kim
    Abstract:

    ADP-Ribosyl Cyclase (ADPR-Cyclase) produces a Ca2+-mobilizing second messenger, cADP-ribose (cADPR), from NAD+. In this study, we investigated the molecular basis of ADPR-Cyclase activation in the ...

  • molecular mechanism of ADP Ribosyl Cyclase activation in angiotensin ii signaling in murine mesangial cells
    American Journal of Physiology-renal Physiology, 2008
    Co-Authors: Seonyoung Kim, Rukhsana Gul, Soyoung Rah, Suhn Hee Kim, Sung Kwang Park, Ho Jeong Kwon, Uhhyun Kim
    Abstract:

    ADP-Ribosyl Cyclase (ADPR-Cyclase) produces a Ca2+-mobilizing second messenger cyclic ADP-ribose (cADPR) from NAD+. In this study, we investigated the molecular basis of ADPR-Cyclase activation and...

Timothy F Walseth - One of the best experts on this subject based on the ideXlab platform.

  • transcriptional regulation of cd38 expression by tumor necrosis factor α in human airway smooth muscle cells role of nf κb and sensitivity to glucocorticoids
    The FASEB Journal, 2006
    Co-Authors: Bit Na Kang, Timothy F Walseth, Deepak A Deshpande, K G Tirumurugaan, Yassine Amrani, Reynold A Panettieri, Mathur S Kannan
    Abstract:

    The transmembrane glycoprotein CD38 catalyzes the synthesis of the calcium mobilizing molecule cyclic ADP-ribose from NAD. In human airway smooth muscle (HASM) cells, the expression and function of CD38 are augmented by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), leading to increased intracellular calcium response to agonists. A glucocorticoid response element in the CD38 gene has been computationally described, providing evidence for transcriptional regulation of its expression. In the present study, we investigated the effects of dexamethasone, a glucocorticoid, on CD38 expression and ADP-Ribosyl Cyclase activity in HASM cells stimulated with TNF-alpha. In HASM cells, TNF-alpha augmented CD38 expression and ADP-Ribosyl Cyclase activity, which were attenuated by dexamethasone. TNF-alpha increased NF-kappaB expression and its activation, and dexamethasone partially reversed these effects. TNF-alpha increased the expression of IkappaBalpha, and dexamethasone increased it further. An inhibitor of NF-kappaB activation or transfection of cells with IkappaB mutants decreased TNF-alpha-induced CD38 expression. The results indicate that TNF-alpha-induced CD38 expression involves NF-kappaB expression and its activation and dexamethasone inhibits CD38 expression through NF-kappaB-dependent and -independent mechanisms.

  • changes in cd38 expression and ADP Ribosyl Cyclase activity in rat myometrium during pregnancy influence of sex steroid hormones
    Biology of Reproduction, 2004
    Co-Authors: Soner Dogan, Deepak A Deshpande, Mathur S Kannan, Timothy F Walseth
    Abstract:

    Cyclic ADP-ribose (cADPR), synthesized by CD38, regulates intracellular calcium in uterine smooth muscle. CD38 is a transmembrane protein that has both ADP-Ribosyl Cyclase and cADPR hydrolase enzyme activities involved in cADPR metabolism. CD38 expression and its enzyme activities in uterine smooth muscle are regulated by estrogen. In the present study, we examined CD38 expression, its enzyme activities, and cADPR levels in myometrium obtained from rats at 14-17 days of gestation (preterm) and at parturition (term). CD38 expression, ADP-Ribosyl Cyclase activity, and cADPR levels were higher in uterine tissues obtained from term rats compared with that of preterm rats, while activity of cADPR hydrolase did not significantly change. In an effort to address whether changes in estrogen: progesterone ratio that occur during pregnancy account for the observed effects on CD38 expression and function, we determined the effect of different doses of progesterone in the presence of estrogen on CD38 expression and its enzyme activities in uterine smooth muscle obtained from ovariectomized rats. In myometrium obtained from ovariectomized rats, estrogen administration caused increased CD38 protein expression and ADP-Ribosyl Cyclase activity. The estrogen-induced increases in CD38 expression and ADP-Ribosyl Cyclase activity were inhibited by simultaneous administration of 10 or 20 mg of progesterone. These results indicate that the estrogen:progesterone ratio determines CD38 expression and ADP-Ribosyl Cyclase activity. These changes in CD38/cADPR pathway may contribute to increased uterine motility and onset of labor.

  • nitric oxide inhibits ADP Ribosyl Cyclase through a cgmp independent pathway in airway smooth muscle
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2002
    Co-Authors: Thomas A White, Timothy F Walseth, Mathur S Kannan
    Abstract:

    There is evidence for a role of cyclic ADP-ribose (cADPR) in intracellular Ca2+ regulation in smooth muscle. cADPR is synthesized and degraded by ADP-Ribosyl Cyclase and cADPR hydrolase, respective...

  • estrogen increases cd38 gene expression and leads to differential regulation of adenosine diphosphate ADP Ribosyl Cyclase and cyclic ADP ribose hydrolase activities in rat myometrium
    Biology of Reproduction, 2002
    Co-Authors: Soner Dogan, Timothy F Walseth, Deepak A Deshpande, Thomas A White, Michael P Murtaugh, Mathur S Kannan
    Abstract:

    Hormones influence uterine contractility through their effects on intracellular calcium. The regulation of intracellular calcium in uterine smooth muscle is achieved by several mechanisms and includes mobilization from intracellular stores by inositol 1,4,5-trisphosphate and ryanodine-sensitive channels. Cyclic ADP-ribose (cADPR), a metabolite of NAD(+), is known to mediate calcium release through ryanodine receptor channels. A cell surface glycoprotein, CD38, catalyzes the synthesis and breakdown of cADPR and thus possesses bifunctional enzymatic activity. The regulation of cADPR synthesis by ADP-Ribosyl Cyclase (Cyclase) or degradation by cADP-ribose hydrolase (hydrolase) by hormones in the myometrium is poorly understood. We investigated the effects of estradiol-17 beta on CD38 expression and the synthesis and degradation of cADPR in myometrial smooth muscle obtained from ovariectomized rats. CD38 expression was studied by reverse transcription polymerase chain reaction and Western blot analyses. In uterine microsomal fractions, Cyclase and hydrolase activities were measured using nicotinamide guanine dinucleotide and [(32)P]cADPR as substrates, respectively. Microsomal proteins subfractionated by SDS-PAGE and gel filtration were used to determine the fractions containing Cyclase and hydrolase activities. The results demonstrate that Cyclase and hydrolase activities are associated with a single protein fraction, similar to CD38 in uteri from both ovariectomized and estradiol-treated rats, and estradiol-17 beta causes 1) increased CD38 mRNA and protein expression and 2) significantly enhanced Cyclase but not hydrolase activity. The differential regulation of CD38 by estradiol-17 beta, resulting in increased cADPR synthesis, would have profound effects on calcium regulation and myometrial contractility.

  • subcellular localization of cyclic ADP Ribosyl Cyclase and cyclic ADP ribose hydrolase activities in porcine airway smooth muscle
    Biochimica et Biophysica Acta, 2000
    Co-Authors: Thomas A White, Hon Cheung Lee, Richard M Graeff, Timothy F Walseth, Sonja E Johnson, Cyrus Munshi, Y S Prakash, Gary C Sieck, Mathur S Kannan
    Abstract:

    Recent studies have provided evidence for a role of cyclic ADP-ribose (cADPR) in the regulation of intracellular calcium in smooth muscles of the intestine, blood vessels and airways. We investigated the presence and subcellular localization of ADP-Ribosyl Cyclase, the enzyme that catalyzes the conversion of beta-NAD(+) to cADPR, and cADPR hydrolase, the enzyme that degrades cADPR to ADPR, in tracheal smooth muscle (TSM). Sucrose density fractionation of TSM crude membranes provided evidence that ADP-Ribosyl Cyclase and cADPR hydrolase activities were associated with a fraction enriched in 5'-nucleotidase activity, a plasma membrane marker enzyme, but not in a fraction enriched in either sarcoplasmic endoplasmic reticulum calcium ATPase or ryanodine receptor channels, both sarcoplasmic reticulum markers. The ADP-Ribosyl Cyclase and cADPR hydrolase activities comigrated at a molecular weight of approximately 40 kDa on SDS-PAGE. This comigration was confirmed by gel filtration chromatography. Investigation of kinetics yielded K(m) values of 30.4+/-1.5 and 695. 3+/-171.2 microM and V(max) values of 330.4+/-90 and 102.8+/-17.1 nmol/mg/h for ADP-Ribosyl Cyclase and cADPR hydrolase, respectively. These results suggest a possible role for cADPR as an endogenous modulator of [Ca(2+)](i) in porcine TSM cells.