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dictyNews Volume 24 Number 07
Dicty News
Electronic Edition
Volume 24, number 7
March 18, 2005
Please submit abstracts of your papers as soon as they have been
accepted for publication by sending them to dicty@northwestern.edu
or by using the form at
http://dictybase.org/db/cgi-bin/dictyBase/abstract_submit.
Back issues of Dicty-News, the Dicty Reference database and other
useful information is available at dictyBase - http://dictybase.org.
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Abstracts
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Effects of valproic acid derivatives on inositol trisphosphate depletion,
teratogenicity, GSK-3{beta} inhibition and viral replication -
A screening approach for new bipolar disorder drugs based on the valproic
acid core structure.
Eickholt BJ, Towers G, Ryves WJ, Eikel D, Adley K, Ylinen L, Chadborn N,
Harwood A, Nau H, Williams RS
Molecular Neurobiology Group (E.B.J., N.H.C.), Medical Research Council
Centre for Developmental Biology, Kingâs College London, London SE1 1UL,
United Kingdom.
Wohl Virion Centre (G.J.T., L.M.J.Y.), Department of Immunology and
Molecular Pathology, University College London, W1T 4JF, United Kingdom.
Medical Research Council Laboratory of Molecular Cell Biology (W.J.R,
A.J.H.) University College London, WC1E6BT, United Kingdom.
Institute for Food Toxicology and Chemical Analysis (D.E., H.N.) Centre of
Systemic Neuroscience, School of Veterinary Medicine Hanover,
30169 Hanover, Germany.
Department of Biology and Wolfson Institute for Biomedical Research (K.A,
R.S.B.W.), University College London, WC1 E6BT, United Kingdom.
Mol Pharmacol, in press
Inositol trisphosphate (InsP3) depletion has been implicated in the
therapeutic action of bipolar disorder drugs including valproic acid (VPA).
It is not currently known if the effect of VPA on InsP3 depletion is related
to the deleterious effects of teratogenicity or elevated viral replication or
if it occurs via putative inhibitory effects on Glycogen Synthase Kinase-3beta
(GSK-3beta). In addition, the structural requirements of VPA-related compounds
to cause InsP3 depletion are unknown. In the current study we have selected a
set of 10 VPA congeners to examine their effects on InsP3 depletion, in vivo
teratogenic potency and their effects on HIV replication and GSK-3beta
activity in vitro. We found four compounds that function to deplete InsP3 in
the model eukaryote Dictyostelium discoideum and these drugs all cause growth
cone enlargement in mammalian primary neurons, consistent with the effect of
InsP3 depletion. No relationship was found between InsP3 depletion and
teratogenic or elevated viral replication effects and none of the VPA
congeners were found to affect GSK-3beta activity. Structural conditions for
InsP3 depletion of VPA congeners are a carboxylic acid function without
dependence on side chain length, branching or saturation. Noteworthy is the
enantiomeric differentiation if a chiral centre exists, suggesting that
InsP3 depletion is mediated by a stereo selective mode of action. Thus the
effect of inositol depletion can be separated from that of teratogenic
potency and elevated viral replication effect. We have used this to identify
two VPA derivatives which share the common InsP3-depleting action of VPA,
lithium and carbamazepine but do not show the side effects of VPA, thus
providing promising novel candidates for bipolar disorder treatment.
Submitted by: Robin Williams [robin.williams@ucl.ac.uk]
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NADPH oxidase homologs are required for normal cell differentiation and
morphogenesis in Dictyostelium discoideum
Bernard Lardy, Mireille Bof, Laurence Aubry, Marie Helene Paclet,
Francoise Morel, Michel Satre and Gerard Klein
BBA Molecular Cell Research, in press
Membrane-associated NADPH oxidase complexes catalyse the production of the
superoxide anion radical from oxygen and NADPH. In mammalian systems, NADPH
oxidases form a family of at least seven isoforms that participate in host
defence and signalling pathways. We report here the cloning and the
characterisation of slime mould Dictyostelium discoideum homologs of the
mammalian heme-containing subunit of flavocytochrome b (gp91phox) (NoxA,
NoxB and NoxC), of the small subunit of flavocytochrome b (p22phox) and of
the cytosolic factor p67phox. Null-mutants of either noxA, noxB, noxC or
p22phox show aberrant starvation-induced development and are unable to
produce spores. The overexpression of NoxAmyc2 in noxA null strain restores
spore formation. Remarkably, the gene alg-2B, coding for one of the two
penta EF-hand proteins in Dictyostelium, acts as a suppressor in noxA, noxB,
and p22phox null-mutant strains. Knockout of alg-2B allows noxA, noxB or
p22phox null-mutants to return to normal development. However, the knockout
of gene encoding NoxC, which contains two penta EF-hands, is not rescued
by the invalidation of alg-2B. These data are consistent with a hypothesis
connecting superoxide and calcium signalling during Dictyostelium development.
Submitted by: Bernard Lardy [BLardy@chu-grenoble.fr]
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Phospholipase D activity is essential for actin localization and actin-based
motility in Dictyostelium
Soha Zouwail, Trevor R.Pettitt*, Stephen K. Dove, Margarita V.
Chibalina1, Dale J. Powner*, Lee Haynes*2, Michael J. O. Wakelam*
and Robert H. Insall**
Biochem. J., in press
Phospholipase D (PLD) activity catalyzes the generation of the lipid messenger
phosphatidic acid, which has been implicated in a number of cellular processes,
particularly the regulation of membrane traffic. In this study, we report that
disruption of PLD signalling causes unexpectedly profound effects on the
actin-based motility of Dictyostelium. Cells in which PLD activity is inhibited
by butan-1-ol show a complete loss of actin-based structures, accompanied by
relocalization of F-actin into small clusters, and eventually the nucleus,
without a visible drop in levels of F-actin. Addition of exogenous phosphatidic
acid reverses the effects of butan-1-ol, confirming that these effects are
caused by inhibition of PLD. Loss of motility correlates with complete
inhibition of endocytosis and a reduction in phagocytosis. Inhibition of PLD
caused a major decrease in the synthesis of PtdIns(4,5)P2, which could again
be reversed by exogenously applied phosphatidic acid. Thus the essential role
of PLD signalling in both motility and endocytosis appears to be directly
mediated via regulation of PtdIns(4)P kinase activity. This implies that
localized, PLD-regulated synthesis of PtdIns(4,5)P2 is essential for
Dictyostelium actin function.
Submitted by: Robert Insall [r.h.insall@bham.ac.uk]
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[End Dicty News, volume 24, number 7] 
