Context-dependent modulation of αβγ and αβδ GABAA receptors by penicillin: Implications for phasic and tonic inhibition

Abstract

SummaryPenicillin, an open-channel blocker of GABA A receptors, was recently reported to inhibit phasic, but not tonic, currents in hippocampal neurons. To distinguish between isoform-specific and contextdependent modulation as possible explanations for this selectivity, the effects of penicillin were evaluated on recombinant GABA A receptors expressed in HEK293T cells. When co-applied with saturating GABA, penicillin decreased peak amplitude, induced rebound, and prolonged deactivation of currents evoked from both synaptic and extrasynaptic receptor isoforms. However, penicillin had isoform-specific effects on the extent of desensitization, reflecting its ability to differentially modulate peak (non-equilibrium) and residual (near-equilibrium) currents. This suggested that the context of activation could determine the apparent sensitivity of a given receptor isoform to penicillin. To test this hypothesis, we explored the ability of penicillin to modulate synaptic and extrasynaptic isoforms that were activated under more physiologically relevant conditions. Interestingly, while currents evoked from synaptic isoforms under phasic conditions (transient activation by a saturating concentration of GABA) were substantially inhibited by penicillin, currents evoked from extrasynaptic isoforms under tonic conditions (prolonged application by a sub-saturating concentration of GABA) were minimally affected. We therefore concluded that the reported inability of penicillin to modulate tonic currents could not simply be attributed to insensitivity of extrasynaptic receptors, but rather, reflected an inability to modulate these receptors in their native context of activation.

The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors

“…Despite this disparity in receptor composition, the differential effect of penicillin on phasic and tonic GABAergic inhibition is not due only to subunit specificity of the antibiotic. Even though penicillin causes less inhibition in δ‐containing than in γ2‐containing receptors, the preferential block of phasic inhibition is also related to the conditions of receptor activation: currents evoked by high GABA concentrations are reduced to a greater extent than currents elicited by lower concentrations, and peak current amplitudes are efficiently diminished, whereas steady state current levels are hardly affected . Thus, the results obtained in hippocampal neurons in the presence of penicillin do not permit unequivocal conclusions regarding the GABA A receptor subtype preference of retigabine.…”

Etomidate uniquely modulates the desensitization of recombinant α1β3δ GABAA receptors

“…Given that native α1βδ receptors mediate GABAergic tonic currents in response to constant GABA exposure (Glykys et al, 2007), we examined the effects of etomidate on β3-α1-δ/β3-α1 receptor “steady state” currents (Feng et al, 2009). The effects of etomidate on peak vs. steady-state currents of β3-α1-δ/β3-α1 receptors were compared in experiments using prolonged GABA applications (30 s) (Figure 3A, C).…”

The wake-promoting transmitter histamine preferentially enhances alpha-4 subunit-containing GABAA receptors

“…For example, open channel block by penicillin shows distinct features at high versus low GABA concentration(Feng et al, 2009), neurosteroid modulation is highly dependent on GABA concentration(Bianchi and Macdonald, 2003), and the effects of benzodiazepines on opening frequency depend on synaptic versus steady state conditions(Bianchi et al, 2009a). In each case, previously described drug actions could be (in part) explained by the experimental conditions.…”