Effects of ivermectin on the activation and desensitization of the human GABAA receptor

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Ivermectin is a widely-used antiparasitic drug that acts through allosteric activation and potentiation of the glutamate-gated chloride channel present in neurons and muscle cells of helminths and insects.In mammals, ivermectin activates several members of the Cys-loop ion channel family including the GABA A receptor.While the centrally located GABA A receptors are protected against the actions of ivermectin by the transporter protein P-glycoprotein 1 present in the blood-brain barrier, the many peripheral GABA A receptors are exposed to blood-borne ivermectin.Here, we have investigated the activating and modulatory effects of ivermectin on α5β3γ2L and α1β3γ2L GABA A receptors expressed in Xenopus oocytes.We show that ivermectin is a potent and efficacious agonist of the α5β3γ2L receptor with an EC 50 of 0.06 μM and the maximal probability of being in the active state >0.3.Ivermectin, unlike typical agonists of the GABA A receptor, does not desensitize the receptor even in 20-min long applications.Receptors desensitized by high concentrations of GABA are re-activated upon exposure to ivermectin.Coapplication of ivermectin with GABA or the allosteric agonist etomidate manifests as simple additivity of individual responses rather than potentiation.The application of the allosteric agonist pentobarbital is without effect or reduces the response to ivermectin.Overall, GABA A receptor activation by ivermectin exhibits a number of unique properties not encountered with commonly used or studied GABAergic drugs. Significance statementPeripheral GABA A receptors are accessible to the widely used antiparasitic agent ivermectin.We show that ivermectin activates the α5β3γ2L and α1β3γ2L subtypes at therapeutic concentrations.Responses to ivermectin are not potentiated by the transmitter GABA or the allosteric agonists etomidate or pentobarbital.Receptors activated by ivermectin do not exhibit desensitization while receptors desensitized by GABA are re-activated upon exposure to ivermectin.

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