Snake Toxins and their Use as Pharmacological Modulators of GABAa Receptors

Ionotropic γ-aminobutyric acid type A (GABAA) receptors are found primarily in the central nervous system (CNS) where they mediate inhibitory post-synaptic transmission by increasing CI^" conductance into the cell. However, GABAA receptor activation can be excitatory in neonatal neurons and dorsal root ganglia where intracellular CI^" concentrations are high and receptor activation causes CI^" efflux which in turn, depolarizes the cell. When the balance between excitatory and inhibitory GABAA receptor activity is shifted due to abnormal function, clinical phenotypes such as epilepsy, schizophrenia, and chronic pain can occur. As such, GABAA receptors are targeted by various drugs including barbiturates, benzodiazepines, and anesthetics. JHU researcvhers discovered two toxins present in Costa Rican coral snake venom, named MmTXl and MmTX2, which bind to GABAA receptors at nanomolar concentrations. Studies with recombinant and synthetic toxin variants on hippocampal neurons and cells expressing common receptor compositions show that MmTXl and MmTX2 and polypeptide homologs and variants thereof, can potentiate GABAA receptor opening and accelerate desensitization when an agonist is present, possibly by interacting with the α+/β- interface.

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