MmTX1 and MmTX2 from coral snake venom potently modulate GABA _A receptor activity

Abstract

GABA A receptors shape synaptic transmission by modulating Cl − conductance across the cell membrane. Remarkably, animal toxins that specifically target GABA A 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 GABA A 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 GABA A 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 GABA A receptor sensitivity to agonist, thereby establishing a previously unidentified class of tools to study this receptor family.

A tale of ligands big and small: An update on how pentameric ligand-gated ion channels interact with agonists and proteins

“…However, examples among pLGICs have remained scarce, with the exception of the reasonably well-characterised interactions of the orthosteric binding site of nAChRs with α-bungarotoxin and conotoxins [74]. A recent breakthrough came from the discovery of the first GABAR-specific toxins from coral snake venom [75], which potently modulate GABA A R activity. Although these particular peptides will likely serve mostly as tool compounds to decipher GABAergic synaptic transmission, they could serve as a starting point to target the dazzling variety of GABA A Rs with more specific therapeutics in the future.…”

High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method

“…For other Cys-loop receptors, information about bioactive peptides that target them is scarce. However, the GABA-A receptor should be mentioned here: a decade ago, it was found that one subtype could bind the αBgt51 and it was recently shown that this receptor also binds the αCtx50 and some other snake venom neurotoxins5253. Moreover, although with a low affinity, the GABA-A receptor can bind the α-conotoxin ImI, which interacts with the α7 nAChR50.…”

The three‐finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions

“…Recently, toxins MmTX1 and MmTX2 from coral snake ( Micrurus mipartitus) venom were found to allosterically modulate the GABA A receptor activity, leading to a potentiation of the receptor opening and desensitization by the agonist (Rosso et al . ). In conclusion, the number of receptors, channels, and enzymes targeted by 3FTs is increasing continuously, expanding our knowledge and highlighting the unique capacity of this fold to trigger pleiotropic functions.…”