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

Ivermectin (IVM) 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, IVM activates several members of the Cys-loop ion channel family, including the GABA_A receptor. Although the centrally located GABA_A receptors are protected against the actions of IVM by the transporter protein P-glycoprotein 1 present in the blood-brain barrier, many peripheral GABA_A receptors are exposed to blood-borne IVM. Here, we have investigated the activating and modulatory effects of IVM on α5β3γ2L and α1β3γ2L GABA_A receptors expressed in Xenopus oocytes. We show that IVM is a potent and efficacious agonist of the α5β3γ2L receptor with an EC₅₀ of 0.06 μM and a maximal probability of being in the active state >0.3. IVM, unlike typical agonists of the GABA_A receptor, does not desensitize the receptor even in 20-minute-long applications. Receptors desensitized by high concentrations of GABA are reactivated upon exposure to IVM. Coapplication of IVM 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 IVM. Overall, GABA_A receptor activation by IVM exhibits a number of unique properties not encountered with commonly used or studied GABAergic drugs. SIGNIFICANCE STATEMENT: Peripheral GABA_A receptors are accessible to the widely used antiparasitic agent ivermectin (IVM). This study shows that IVM activates the α5β3γ2L and α1β3γ2L subtypes at therapeutic concentrations. Responses to IVM are not potentiated by the transmitter GABA or the allosteric agonists etomidate or pentobarbital. Receptors activated by IVM do not exhibit desensitization, while receptors desensitized by GABA are reactivated upon exposure to IVM.