Artículos de revistas
MmTX1 and MmTX2 from coral snake venom potently modulate GABAA receptor activity
Fecha
2015-02-24Registro en:
1091-6490
10.1073/pnas.1415488112
25675485
PMC4345566
Autor
Rosso Julien, Jean Pierre
Schwarz, Jürgen R.
Diaz Bustamante, Marcelo
Céard, Brigitte
Gutiérrez, José María
Kneussel, Matthias
Pongs, Olaf
Bosmans, Frank
Bougis, Pierre Edouard
Institución
Resumen
GABAA receptors shape synaptic transmission by modulating Cl− conductance across the cell membrane. Remarkably, animal toxins that specifically target GABAA receptors have not been identified. Here, we report the discovery of micrurotoxin1 (MmTX1) and MmTX2, two toxins present in Costa Rican coral snake venom that tightly bind to GABAA receptors at subnanomolar concentrations. Studies with recombinant and synthetic toxin variants on hippocampal neurons and cells expressing common receptor compositions suggest that MmTX1 and MmTX2 allosterically increase GABAA receptor susceptibility to agonist, thereby potentiating receptor opening as well as desensitization, possibly by interacting with the α+/β− interface. Moreover, hippocampal neuron excitability measurements reveal toxin-induced transitory network inhibition, followed by an increase in spontaneous activity. In concert, toxin injections into mouse brain result in reduced basal activity between intense seizures. Altogether, we characterized two animal toxins that enhance GABAA receptor sensitivity to agonist, thereby establishing a previously unidentified class of tools to study this receptor family.