Dataset Information

Neurotoxins from snake venoms and ?-conotoxin ImI inhibit functionally active ionotropic ?-aminobutyric acid (GABA) receptors.

ABSTRACT: Ionotropic receptors of ?-aminobutyric acid (GABAAR) regulate neuronal inhibition and are targeted by benzodiazepines and general anesthetics. We show that a fluorescent derivative of ?-cobratoxin (?-Ctx), belonging to the family of three-finger toxins from snake venoms, specifically stained the ?1?3?2 receptor; and at 10 ?m ?-Ctx completely blocked GABA-induced currents in this receptor expressed in Xenopus oocytes (IC50 = 236 nm) and less potently inhibited ?1?2?2 ? ?2?2?2 > ?5?2?2 > ?2?3?2 and ?1?3? GABAARs. The ?1?3?2 receptor was also inhibited by some other three-finger toxins, long ?-neurotoxin Ls III and nonconventional toxin WTX. ?-Conotoxin ImI displayed inhibitory activity as well. Electrophysiology experiments showed mixed competitive and noncompetitive ?-Ctx action. Fluorescent ?-Ctx, however, could be displaced by muscimol indicating that most of the ?-Ctx-binding sites overlap with the orthosteric sites at the ?/? subunit interface. Modeling and molecular dynamic studies indicated that ?-Ctx or ?-bungarotoxin seem to interact with GABAAR in a way similar to their interaction with the acetylcholine-binding protein or the ligand-binding domain of nicotinic receptors. This was supported by mutagenesis studies and experiments with ?-conotoxin ImI and a chimeric Naja oxiana ?-neurotoxin indicating that the major role in ?-Ctx binding to GABAAR is played by the tip of its central loop II accommodating under loop C of the receptors.

SUBMITTER: Kudryavtsev DS

PROVIDER: S-EPMC4566246 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neurotoxins from snake venoms and α-conotoxin ImI inhibit functionally active ionotropic γ-aminobutyric acid (GABA) receptors.

Kudryavtsev Denis S DS Shelukhina Irina V IV Son Lina V LV Ojomoko Lucy O LO Kryukova Elena V EV Lyukmanova Ekaterina N EN Zhmak Maxim N MN Dolgikh Dmitry A DA Ivanov Igor A IA Kasheverov Igor E IE Starkov Vladislav G VG Ramerstorfer Joachim J Sieghart Werner W Tsetlin Victor I VI Utkin Yuri N YN

The Journal of biological chemistry 20150728 37

Ionotropic receptors of γ-aminobutyric acid (GABAAR) regulate neuronal inhibition and are targeted by benzodiazepines and general anesthetics. We show that a fluorescent derivative of α-cobratoxin (α-Ctx), belonging to the family of three-finger toxins from snake venoms, specifically stained the α1β3γ2 receptor; and at 10 μm α-Ctx completely blocked GABA-induced currents in this receptor expressed in Xenopus oocytes (IC50 = 236 nm) and less potently inhibited α1β2γ2 ≈ α2β2γ2 > α5β2γ2 > α2β3γ2 an ...[more]

PMID: 26221036

Similar Datasets

Project description:There is limited information on the cross-neutralisation of neurotoxic venoms with antivenoms. Cross-neutralisation of the in vitro neurotoxicity of four Asian and four Australian snake venoms, four post-synaptic neurotoxins (?-bungarotoxin, ?-elapitoxin-Nk2a, ?-elapitoxin-Ppr1 and ?-scutoxin; 100 nM) and one pre-synaptic neurotoxin (taipoxin; 100 nM) was studied with five antivenoms: Thai cobra antivenom (TCAV), death adder antivenom (DAAV), Thai neuro polyvalent antivenom (TNPAV), Indian Polyvalent antivenom (IPAV) and Australian polyvalent antivenom (APAV). The chick biventer cervicis nerve-muscle preparation was used for this study. Antivenom was added to the organ bath 20 min prior to venom. Pre- and post-synaptic neurotoxicity of Bungarus caeruleus and Bungarus fasciatus venoms was neutralised by all antivenoms except TCAV, which did not neutralise pre-synaptic activity. Post-synaptic neurotoxicity of Ophiophagus hannah was neutralised by all antivenoms, and Naja kaouthia by all antivenoms except IPAV. Pre- and post-synaptic neurotoxicity of Notechis scutatus was neutralised by all antivenoms, except TCAV, which only partially neutralised pre-synaptic activity. Pre- and post-synaptic neurotoxicity of Oxyuranus scutellatus was neutralised by TNPAV and APAV, but TCAV and IPAV only neutralised post-synaptic neurotoxicity. Post-synaptic neurotoxicity of Acanthophis antarcticus was neutralised by all antivenoms except IPAV. Pseudonaja textillis post-synaptic neurotoxicity was only neutralised by APAV. The ?-neurotoxins were neutralised by TNPAV and APAV, and taipoxin by all antivenoms except IPAV. Antivenoms raised against venoms with post-synaptic neurotoxic activity (TCAV) cross-neutralised the post-synaptic activity of multiple snake venoms. Antivenoms raised against pre- and post-synaptic neurotoxic venoms (TNPAV, IPAV, APAV) cross-neutralised both activities of Asian and Australian venoms. While acknowledging the limitations of adding antivenom prior to venom in an in vitro preparation, cross-neutralization of neurotoxicity means that antivenoms from one region may be effective in other regions which do not have effective antivenoms. TCAV only neutralized post-synaptic neurotoxicity and is potentially useful in distinguishing pre-synaptic and post-synaptic effects in the chick biventer cervicis preparation.

Dataset Information

Neurotoxins from snake venoms and ?-conotoxin ImI inhibit functionally active ionotropic ?-aminobutyric acid (GABA) receptors.

Publications

Neurotoxins from snake venoms and α-conotoxin ImI inhibit functionally active ionotropic γ-aminobutyric acid (GABA) receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets