Aminergic toxins: What they are, what they do and what we can do with

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  • Abstracts / Toxicon 75 (2013) 205223214b Laboratoire de Toxines Alimentaires, Institut Pasteur de Tunis, 13 PlacePasteur, B.P. 74, 1002 Tunis-Belvdre, TunisiacDepartment of Chemistry and Biochemistry, University of California, SantaBarbara, CA 93106-9510, USAA multimodal minimally-invasive approach was un-dertaken to study the local effects of some cyclic iminesbelonging to the families of gymnodimines, spirolides andpinnatoxins (gymnodimine-A, 13-desmethyl C spirolide,pinnatoxin-A and pinnatoxin-G), in vivo, on the neuro-muscular system excitability properties of anesthetizedSwiss-Webster mice. For this purpose, sub-lethal doses ofthe cyclic imines were administered in the tail muscle, as asingle intramuscular injection, and the compound muscleaction potential was recorded in response to caudal motornerve stimulation. The main effect of these phycotoxinswas a marked reversible time- and dose-dependentdecrease of the compound muscle action potential recor-ded from the tail muscle in response to motor nervestimulation. The dose-response curves for the cyclic iminesstudied on the maximal amplitude of the compoundmuscle action potential revealed 50% inhibitory doses of 51ng/mouse (i.e. 1.6 mg/kg or 3.3 nmol/kg) for gymnodimine-A, 0.18 ng/mouse (i.e. 6 ng/kg or 0.01 nmol/kg) for 13-desmethyl C spirolide, 57.3 ng/mouse (i.e. 2.2 mg/kg or 3.1nmol/kg) for pinnatoxin-A, and 66.2 ng/mouse (i.e. 2.2 mg/kg or 2.7 nmol/kg) for pinnatoxin-G. Interestingly, onequimolar basis, 13-desmethyl C spirolide was about 300fold more active than the other three cyclic imines studied.The blocking effect occurred without any significantmodification of other muscle or nerve excitability param-eters. In conclusion, the inhibition of the compoundmuscleaction potential induced by the studied cyclic imines iscompatible with an action of these phycotoxins on neuro-muscular transmission, at the level of the neuromuscularjunction, where they interact and block the muscle-type(a12b1gd) nicotinic acetylcholine receptors.

    We thank the CNRS-DGRS cooperative program for supporting thescientific exchange between France and Tunisia.

    http://dx.doi.org/10.1016/j.toxicon.2013.08.026Aminergic toxins: What they are, what they do andwhat we can do with

    G. Blanchet a,b, G. Collet a,c, N. Gilles a, G. Mourier a,D. Servent aa CEA, Institute of Biology and Technology (iBiTec-S), Service d'IngnierieMolculaire des Protines (SIMOPRO), Gif-sur-Yvette 91191, FrancebUFR Sciences de la Vie, Universit Pierre et Marie Curie (UPMC), 4 placeJussieu, Paris, Francec IRISA (CNRS & Univ Rennes 1), Inria Rennes, Dyliss team, Bat 12, Campus deBeaulieu, 35042 Rennes cedex, FranceAnimal venoms are complex mixtures of polypeptidesand enzymes that form large structural multigene familiesthat at the end could form multifunctional family. Despitemany decades of intensive research about animal venoms,the majority of the toxins identified until now interactswith ionic channels which play crucial role in the neuro-transmission process (like voltage-gated calcium, potassiumor sodium channels). In snake venom, a typical example of amultigene andmultifunctional family can be the three-fingertoxin (3FTx) family. With more than 450 toxins identified,sharing a common three-finger fold (60 to 80 residueswith 4disulfidebridges in a globular core fromwhich emerges threeloops called finger structured in beta strand), 3FTx arecomposed by a huge number of the basal neurotoxins (type Iand II alpa-neurotoxins, kappa-neurotoxins), acting on thediverse types of nicotinic acetylcholine receptors, and fewminor groupswithother (called derivative) functions (suchas fasciculin acting on acetylcholinesterase enzyme, cyto-toxin interactingwith the cell membrane and others). In thisway, the genus Dendroaspis (African mamba) has evolved anatypical set of 3FTx in term of derivative functions: themuscarinic and adrenergic toxins, acting on G protein-coupled receptors (GPCR) (muscarinic and adrenergic re-ceptors respectively). Despite their important roles in almostall biological functions, this large membrane protein family(up to 1000members in human) is not, for instance, classicalvenom target. We have investigated the ability of differentmuscarinic and adrenergic toxins to interact with the humanaminergicGPCR family (composedby30membersbelongingto 5 subfamilies), localized in the central and peripheralnervous system where they are involved in various physio-logical processes such as cognition, neuronal development,endocrine regulation or vascular system regulation. Ourpharmacological results, based on binding experiments,show that toxins previously described as muscarinic toxins,like MT1 and MT3 can also interact very efficiently withvarious subtypes of alpha 1 and alpha 2 adrenoceptors.Coupled with our phylogenetic analysis, showing thatMuscarinic and Adrenergic toxins are clustered togetherwithout distinction of targeting, we can break these twogroups and form a new monophyletic group: the aminergictoxins. In the view of design selective ligand, that can beuseful tools for deciphering biological functions of GPCR, wehave alsoengineered aminergic toxins inorder to designnewselective toxins with desired pharmacological profiles. Toconclude, mamba can produce 3FTx with an atypical, butbiologically relevant, human target: the aminergic GPCRsystem. These toxins, named aminergic toxins, could beuseful tools to design new selective ligands.

    http://dx.doi.org/10.1016/j.toxicon.2013.08.027Characterization of the first potassium channel blockersfrom the venom of the Morocan scorpion Buthusoccitanus Paris

    M.F. Martin-Eauclaire a, B. Ceard a, M. Belghazi b,R. Lebrun c, P.E. Bougis a,ba CNRS/AMU CRN2M UMR 7286, FrancebCAPM-PFRN CRN2M UMR 7286, Francec Plateforme Protomique IMM FR3479, Marseille Protomique (IBiSA), Aix-Marseille Universit, Marseille, FranceThe availability of a large variety of specific blockers,which inhibit different K+ currents, would help to elucidatetheir differences in physiologic function. Short peptide toxinsisolated from scorpion venoms are able to block voltage-

    http://dx.doi.org/10.1016/j.toxicon.2013.08.026http://dx.doi.org/10.1016/j.toxicon.2013.08.027

    Aminergic toxins: What they are, what they do and what we can do withCharacterization of the first potassium channel blockers from the venom of the Morocan scorpion Buthus occitanus Paris