Reduced activation of the synaptic-type GABAA receptor following prolonged exposure to low concentrations of agonists: Relationship between tonic activity and desensitization

Spencer R. Pierce, Allison L. Germann, Alex S. Evers, Joe Henry Steinbach, Gustav Akk

Research output: Contribution to journalArticlepeer-review


Synaptic GABAA receptors are alternately exposed to short pulses of a high, millimolar concentration of GABA and prolonged periods of low, micromolar concentration of the transmitter. Prior work has indicated that exposure to micromolar concentrations of GABA can both activate the postsynaptic receptors generating sustained low-amplitude current and desensitize the receptors, thereby reducing the peak amplitude of subsequent synaptic response. However, the precise relationship between tonic activation and reduction of peak response is not known. Here, we have measured the effect of prolonged exposure to GABA or the combination of GABA and the neurosteroid allopregnanolone, which was intended to desensitize a fraction of receptors, on a subsequent response to a high concentration of agonist in human a1b3g2L receptors expressed in Xenopus oocytes. We show that the reduction in the peak amplitude of the post-exposure test response correlates with the open probability of the preceding desensitizing response. Curve fitting of the inhibitory relationship yielded an IC50 of 12.5 mM and a Hill coefficient of 21.61. The activation and desensitization data were mechanistically analyzed in the framework of a three-state Resting-Active-Desensitized model. Using the estimated affinity, efficacy, and desensitization parameters, we calculated the amount of desensitization that would accumulate during a long (2-minute) application of GABA or GABA plus allopregnanolone. The results indicate that accumulation of desensitization depends on the level of activity rather than agonist or potentiator concentration per se. We estimate that in the presence of 1 mM GABA, approximately 5% of a1b3g2L receptors are functionally eliminated because of desensitization.

Original languageEnglish
Pages (from-to)762-769
Number of pages8
JournalMolecular pharmacology
Issue number6
StatePublished - Dec 1 2020


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