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Symposium on “toxins and ion
Thursday 27 July
“Mechanisms and specificity in the
interaction of scorpion toxins with
voltage-gated sodium channels”
Michael Gurevitz was born in 1946 in Germany and received his BS, MSc and PhD
degrees at the Hebrew University of Jerusalem. He spent six years (1981-1986) in the
United States before he joined Tel Aviv University, where he serves now as a Professor at
The Department of Plant Sciences. His interests divide between Toxinology and plant
molecular biology. In the early 90s he has established a successful expression system for
scorpion toxins affecting voltage-gated sodium channels, which has been used
extensively to study structure-activity relationship and the mechanism by which these
toxins interact with their target channels.
The Gurevitz laboratory focuses in their toxinology research on molecular mechanisms
underlying the mode of action and specific recognition of insect and mammalian Na+
channels by a variety of pharmacologically distinct scorpion toxins. This study is motivated
by the need to develop new approaches to the design of environmentally-safe,
biodegradable insecticides and selective drugs in medicine. The experimental approach
combines methods of various disciplines (molecular genetics, neuropharmacology,
electrophysiology, structural biology) and involves extensive collaboration with several
research groups in Israel and abroad. Selected publications (from the last 2 years)
Cohen L, Karbat I, Gilles N, Froy O, Corzo G, Angelovici R, Gordon D & Gurevitz M (2004) Dissection of the functional surface of an anti-insect excitatory toxin illuminates a putative ‘hot spot’ common to all scorpion α-toxins affecting Na+ channels. J Biol Chem
279:8206-8211. Karbat I, Cohen L, Gilles N, Gordon D & Gurevitz M (2004) Conversion of a scorpion toxin agonist into an antagonist highlights an acidic residue involved in voltage sensor trapping during activation of neuronal Na+ channels. FASEB J
18:683-689. Karbat I, Frolow F, Froy O, Gilles N, Cohen L, Turkov M, Gordon D & Gurevitz M (2004) Molecular basis of the high insecticidal potency of scorpion α-toxins. J Biol Chem
279:31679-31686. Tan J, Liu Z, Wang R, Huang Z, Chen AC, Gurevitz M & Dong K (2005) Identification of amino acid residues critical for pyrethroid binding to insect sodium channels. Mol Pharmacol
67:513-522. Corzo G, Escoubas E, Villegas E, Karbat I, Gordon D, Gurevitz M, Nakajima T & Gilles N (2005) A spider toxin that induces a typical effect of scorpion α-toxins but competes with β-toxins on binding to insect sodium channels. Biochemistry
44:1542-1549. Cohen L, Karbat I, Gilles N, Ilan N, Gordon D & Gurevitz M (2005) Common features in the functional surface of scorpion β-toxins and elements that confer specificity for insect and mammalian voltage-gated Na-channels. J Biol Chem
280:5045-5053. Strugatsky D, Zilberberg N, Ilan N, Turkov M, Cohen L, Stankiewicz M, Pelhate M, Gilles N, Gordon D & Gurevitz M (2005) Expression of a gene family encoding a novel scorpion depressant toxin illuminates the key role of asparagine-58 in activity on insect neuronal sodium channels. Biochemistry
Symposium on “toxins
and ion channels”
Thursday 27 July
“Glycerotoxin, a new
tool to dissect synaptic
Dr Meunier’s research focuses on understanding, at the molecular level, the dynamics
events mediating neuronal/hormonal secretions and synaptic plasticity (how neurons
survive, connect and communicate). To study these fundamental physiological processes,
two main strategies are used: first, taking advantage of the exquisite selectivity of
neurotoxins to selectively dissect these mechanisms, and second, examining the role
played by members of certain classes of lipid in modulating various steps of neuronal
secretions. The hope is to establish novel avenues in our understanding of neuronal
communications that will lead to novel therapeutic strategies to tackle neuronal diseases. Selected Publications:
Rickman, C., Meunier, F. A., Binz, T. and Davletov, B. A. (2004). High affinity interaction of
syntaxin and SNAP-25 on the plasma membrane is abolished by botulinum toxin E. J. Biol.
Foran, P.G., Davletov, B., and Meunier F. A. (2003). Getting muscles moving again after
botulinum toxin : novel therapeutic challenges. Trends in Molecular Medicine 9: 9291-9299.
Meunier, F.A., Feng, Z.P., Molgo, J., Zamponi, G. and Schiavo G. (2002). Glycerotoxin from Glycera convoluta
stimulates neurosecretion by targeting N-type Ca2+ channels Cav2.2. EMBO
J. 21: 6733-6743.
Osborne, S.L., Meunier, F. A. and Schiavo G. (2001). Phosphoinositides as Key Regulators of
Synaptic Function. Neuron 32: 9-12.
Symposium on “toxins and ion
Thursday 27 July
“Potassium channel toxins - a
trail from cortex to channel
BSc (Hons) Aberdeen University, 1982; PhD, John Curtin School of Medical Research,
Australian National University 1986; Postdoctoral Fellow, Sandoz Institute 1986-1988;
Principal Scientist, Wyeth Research UK 1988- 1994; Governors’ Lecturer, Biochemistry,
Imperial College London 1995- 2002; Professor of Neuroscience, University of Strathclyde
2002-2004; Eberhard Buhl Chair of Neurobiology, University of Leeds (2004 - ); Wellcome
Trust Neurosciences and Mental Health Committee; Scientific Advisory Board, Biofocus
PLC; MRC Brain Sciences Panel; Reviewing and Topical Reviews Senior Editor, Journal
Research programme: Understanding the role of neuronal ion channels
The challenge of understanding brain and neuronal function in health and disease
requires an interdisciplinary attack at multiple levels, from genomic information through
molecular, cellular and systems approaches. My background is in physiology with my
present research focussing mainly on the characterization of voltage-gated potassium
channels. Potassium channels are crucial regulators of the excitability of nerve cells, and
they have consequently become an important target for academic and drug research.
Indeed, I first worked on these in the pharmaceutical industry. My interests and
experience ranges from obscure biophysical measurements of channel function up to
complex neuronal networks in brain slices and isolated, intact, cerebellum. Throughout
my career, I’ve come back again and again to using toxins as selective tools to dissect out
roles of specific ion channels. Our lab employs a wide range of techniques and has
developed some novel preparations. At the most basic level, we employ site directed
mutagenesis techniques to unravel which parts of cloned potassium channel subunits
contribute to their opening and their distinctive pharmacology. Furthermore, we examine
‘native’ voltage gated potassium currents in nerve cells, trying to understand the
molecular identity of these using antibody labelling and physiological and pharmacological
‘fingerprinting’ and transgenic animals.
Another major interest in our lab is the study of changes in sensory neurons following
nerve injury. Neuropathic pain is a huge health problem, and unfortunately, despite
intensive study, we still know very little about the fundamental mechanisms involved.
Using animal and organotypic culture models, we are investigating excitability changes
often associated with anatomical remodelling, including sprouting of axonal terminals
around primary afferent somata in dorsal root ganglia. Selected recent publications:
AP SOUTHAN & B ROBERTSON (2000) Electrophysiological characterization of voltage-gated
K+ currents in cerebellar basket and Purkinje cells: Kv1 and Kv3 channel subfamilies are
present in basket cell nerve terminals. Journal of Neuroscience 20,
JM MILLAR, L BARRATT, AP SOUTHAN, KM PAGE, REW FYFFE, B ROBERTSON, & A
MATHIE (2000) A functional role for the two-pore domain potassium channel TASK-1 in
cerebellar granule neurons. Proceedings of the National Academy of Sciences (USA) 97
T BUSHELL, C CLARKE, A MATHIE & B ROBERTSON (2002) Pharmacological
characterisation of a non-inactivating outward current in mouse cerebellar Purkinje neurones. British Journal of Pharmacology 135,
NP MORRIS, REW FYFFE & B ROBERTSON (2004) Characterisation of the
hyperpolarization-activated current (Ih) in the medial septum/diagonal band complex in the
mouse. Brain Research, 1006,
SYM YEUNG, D THOMPSON, Z WANG, D FEDIDA, B ROBERTSON (2005) Modulation of
Kv3 subfamily potassium currents by the sea anemone toxin BDS: Significance for CNS and
biophysical studies. Journal of Neuroscience, 25,
John W. Daly
Thursday 27 July
John W. Daly
“Alkaloids as probes
for ionic channels”
Dr. Daly was born and raised in Portland, Oregon. He received in 1954 a bachelors
degree in Biochemistry and in 1955 a masters degree in Organic Chemistry at Oregon
State College and then a Ph.D. in Organic Chemistry at Stanford University in 1958. After
a two year postdoctorate in the Laboratory of Chemistry at NIH, he became a permanent
member of the staff in 1960, a section chief in 1969 and the founding chief of the
Laboratory of Bioorganic Chemistry in 1981. He became a NIH Scientist Emeritus in
January 2003. During his five decades at NIH, his research has spanned many
disciplines, being involved in isolation, structure elucidation and synthesis of novel natural
products and receptor agonists/ antagonists and in the elucidation of their mechanism of
action with a focus on receptors, ion channels, and second messenger formation in the
nervous system. High points in his career include the discovery of the NIH Shift, the
introduction of a prelabeling technique for investigation of cyclic AMP generation in intact
cells, the introduction of a variety of selective agonists and antagonists as probes and
radioligands for adenosine receptors, the delineation of biological targets for caffeine and
other xanthines in the central nervous system, the discovery of the direct activation of
adenylyl cyclase by forskolin, the discovery of the activation of phosphoinositide
breakdown by maitotoxin, and the discovery that loperamide is a unique modulator of a
capacitative calcium influx pathway and that N-substituted dihydropyridines are selective
blockers of such channels. Over four decades, he has been involved both in field
collection and as a chemist and pharmacologist in the discovery and structure elucidation
of a wide range of over 800 alkaloids of twenty some structural classes in amphibian skin
and elucidation of the basis for their biological activity. Such compounds include
batrachotoxins, histrionicotoxins, pumiliotoxins, and epibatidine. Certain of these
alkaloids are now widely used as research tools; batrachotoxin as a selective activator of
sodium channels, histrionicotoxins as blockers of nicotinic channels, pumiliotoxins as
sodium channel agents with biomedical potential as cardiotonic agents and epibatidine as
nicotinic agonist with potent analgetic activity. Analogues of epibatidine are the subject of
clinical trials for a treatment of chronic pain of neuropathies, cancer and arthritis. Many of
the alkaloids discovered by Dr. Daly have been the target of synthetic research in
laboratories world-wide. Dr. Daly’s research presently focuses on the structure and
biological activity of further novel alkaloids found in amphibian skin and on the dietary
origin of such alkaloids. Dr. Daly has been the recipient of other awards in recognition of
his achievements. He was elected to the National Academy of Sciences, USA in 1997.
Besides his abiding interest in field work and research, Dr. Daly is an avid fisherman.
Selected publications from a bibliography of over 600 articles and reviews follow.
1. Seamon, K.B., and Daly, J.W.: Forskolin: A unique diterpene activator of cyclic AMP-
generating systems. J. Cyclic Nucleotide Res. 7
: 201-224, 1982.
2. Badio, B., and Daly, J.W. Epibatidine, a potent analgetic and nicotinic agonist. Mol
: 563-569, 1994.
3. Daly, J.W., Kaneko, T., Wilham, J., Garraffo, H.M., Spande, T.F., A. Espinosa and Donnelly,
M.A. Bioactive alkaloids of frog skin: Combinatorial bioprospecting reveals that pumiliotoxins
have an arthropod source. Proc. Natl. Acad. Sci. U.S.A. 99
: 13996-14001, 2002.
4. Daly, J.W. Ernest Guenther Award in Chemistry of Natural Products. Amphibian skin: A
remarkable source of biologically active arthropod alkaloids. J. Med. Chem. 46
5. Fitch, R.W., Garraffo, H.M., Spande, T.F., Yeh, H.J.C. and Daly, J.W. Bioassay-guided
isolation of epiquinamide, a novel quinolizidine alkaloid and nicotinic agonist from an
Ecuadoran poison frog, Epipedobates tricolor
. J. Nat. Prod. 66
: 1345-1350, 2003.
6. Dumbacher, J.P., Wako, A., Derrickson, S.R., Samuelson, A., Spande, T.F., and Daly, J.W.
Melyrid beetles (Choresine)
: A putative source for the batrachotoxin alkaloids found in poison-
dart frogs and toxic passerine birds. Proc. Natl. Acad. Sci. U.S.A. 101
: 15857-15860, 2004.
7. Daly, J.W., Spande, T.F., and Garraffo, H.M. Alkaloids from amphibian skin: A
tabulation of over eight-hundred compounds. J. Nat. Prod. 68
: 1556-1575, 2005.
Thursday 27 July
“Ion channels, toxins,
Michel Lazdunski is professor at the Medical School of the University of Nice – Sophia Antipolis He holds the chair of Molecular Pharmacology at the Institut Universitaire de France. A world-renowned specialist of ion channels, Michel Lazdunski and his team have made internationally recognized contributions to basic research and to applied research in pharmacology and pathology. These range from understanding the mechanisms underlying oral antidiabetics, and inhalational anesthetics, to the mechanisms of pain perception, cardiac arrhythmia, convulsions, and cerebral ischemia. Over the last 30 years, Michel Lazdunski and his group have introduced and/or analyzed the machanisms of a large variety of toxins, particularly toxins for voltage-sensitive Na+ channels, voltage-sensitive K+ channels, Ca2+-sensitive K+ channels, voltage-sensitive Ca2+ channels and ASIC channels. They have also worked on several other types of venom polypeptides among which toxic phospholipases A2. Michel Lazdunski earned a degree in chemical engineering in 1959, followed by a Ph. D. in physical chemistry in 1962, and a doctorate in biochemistry (doctorat ès sciences) in 1964. He joined the CNRS in 1962. When the CNRS Center for Biochemistry and Molecular Biology opened in 1967 in Marseilles, he took charge of the research group studying the physical chemistry of proteins and enzymology, which he oversaw until 1973. He then created the CNRS Center for Biochemistry in Nice and directed it until 1989, when he founded the CNRS Institute of Molecular and Cell Pharmacology (Institut de pharmacologie moléculaire et cellulaire, IPMC) in Sophia Antipolis, a high tech campus near Nice.
Michel Lazdunski received the CNRS Silver Medal in 1976 for his work on enzymology and the structure of proteins. He has received several prestigious awards, such as the Grand Prix of the French Academy of Sciences for biological research (Charles Léopold Mayer Prize) in 1983, the International Society for Cardiac Research Award in 1984, the Athena Foundation - Institut de France Prize in 1991, the Grand Prix of the French Foundation for Medical Research in 2003. Also in 1991, his team received the Bristol-Myers Foundation Neuroscience Award. Michel Lazdunski is a member of several academies, including the Academia Europaea (1989), the French Academy of Sciences (1991), the Belgian Royal Academy of Medicine (1991). He was awarded the CNRS Gold Medal (2000).
Some recent publications
Diochot S, Baron A, Rash LD, Deval E, Escoubas P, Scarzello S, Salinas M, Lazdunski M.
(2004). A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel
in sensory neurons. EMBO J. 23:1516-25.
Chagot B, Escoubas P, Villegas E, Bernard C, Ferrat G, Corzo G, Lazdunski M,
Darbon H. (2004). Solution structure of Phrixotoxin 1, a specific peptide inhibitor of Kv4
potassium channels from the venom of the theraphosid spider Phrixotrichus auratus
Salinas M, Rash LD, Baron A, Lambeau G, Escoubas P, Lazdunski M. (2005).THE
RECEPTOR SITE OF THE SPIDER TOXIN PcTx1 ON THE PROTON-GATED CATION
CHANNEL ASIC1a. J Physiol. in press.
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