The dual modulatory effects of efavirenz on GABA A receptors are mediated via two distinct sites

Abstract

Efavirenz is a widely prescribed medicine used to treat type 1 human immunodeficiency virus (HIV-1), the most prevalent pathogenic strain of the virus responsible for the acquired immune deficiency syndrome (AIDS) pandemic. Under prescribed dosing conditions, either alone or in combination therapy, efavirenz-induced CNS disturbances are frequently reported. Efavirenz was recently reported to interact in a similar concentration range with a number of receptors, transporters and ion channels including recombinant rat α1β2γ2 GABAA receptors whose actions were potentiated (Gatch et al., 2013; Dalwadi et al., 2016). Now we report on the molecular mechanism of efavirenz on GABAA receptors as a function of concentration and subunit composition via whole-cell recordings of GABA-activated currents from HEK293 cells expressing varying subunit configurations of GABAA receptors. Efavirenz elicited dual effects on the GABA response; it allosterically potentiated currents at low concentrations, whereas it inhibited currents at higher concentrations. The allosteric potentiating action on GABAA receptors was pronounced in the α1β2γ2, α2β2γ2 and α4β2γ2 configurations, greatly diminished in the α6β2γ2 configuration, and completely absent in the α3β2γ2 or α5β2γ2 configuration. In stark contrast, the inhibitory modulation of efavirenz at higher concentrations was evident in all subunit configurations examined. Moreover, efavirenz-induced modulatory effects were dependent on GABA concentration ([GABA]), with a pronounced impact on currents activated by low [GABA] but little effect at saturating [GABA]. Mutation of a highly-conserved threonine to phenylalanine in transmembrane domain 2 of the α1 subunit abolished the inhibitory effect of efavirenz in α1β2 receptors. Finally, mutations of any of the three conserved extracellular residues in α1/2/4 subunits to the conserved residues at the corresponding positions in α3/5 subunits (i.e., R84P, M89L or I120L) completely eliminated he potentiating effect of efavirenz in α1β2γ2 configuration. These findings demonstrate that efavirenz’s positive allosteric modulation of the GABAA receptor is mediated via a novel allosteric site associated with the extracellular domain of the receptor.

Depression and Suicidal Ideation Among HIV-Infected Adults Receiving Efavirenz Versus Nevirapine in Uganda

“…Nevertheless, studies associating slower efavirenz clearance with greater CNS toxicity have been conducted in predominantly Caucasian participants (27,28), whereas those done in participants of African ancestry have largely found no association (29–31). Efavirenz has also been shown to interact with multiple neurotransmitter pathways, and host genetic modulation of these pathways could lead to different phenotypic effects (32,33).…”

Coronaridine congeners potentiate GABAA receptors and induce sedative activity in mice in a benzodiazepine-insensitive manner

“…Human (h) α1β2γ2 and hα2β2γ2 GABAARs stably expressed in HEK293 cells were generously provided by John Drewe (Cytovia Inc, San Diego, CA). The pharmacological properties of these receptors have been extensively characterized in our previous publications (Huang et al, 2001;Huang et al, 2004;Huang et al, 2017). On the other hand, hα1β2 and hρ1 GABAARs, and hα1 GlyRs, were transiently transfected in HEK293 cells using PolyJet™ DNA In Vitro and Trans-IT 293 transfection reagents (Snell and Gonzales, 2015;Chen et al, 2017).…”

Prolonged efavirenz exposure reduces peripheral oxytocin and vasopressin comparable to known drugs of addiction in male Sprague Dawley rats

“…Moreover, EFV modulates numerous neurological systems (i.e. serotonergic, muscarinic and GABAergic) that have been suggested to underlie EFV-induced NPAEs ( Dalwadi et al, 2016 ; see Dalwadi et al, 2018 for review; Gatch et al, 2013 ; Huang et al, 2017 ). EFV, at the dose used in this study, also increases striatal DA levels and reward-driven behavior ( Möller et al, 2018 ), thereby implicating dopaminergic reward neurocircuitry in this action.…”