Gamma-aminobutyric acid type A receptor (GABA-A receptor) (GABA-AR)

Neurosteroid-sensitive receptors, primarily represented by the Gamma-aminobutyric acid type A (GABA-A) receptor, are pentameric ligand-gated ion channels that mediate the majority of fast inhibitory neurotransmission in the central nervous system (Belelli & Lambert, 2005). These receptors are uniquely sensitive to endogenous neurosteroids like allopregnanolone, which bind to distinct allosteric sites in the transmembrane domain to enhance the receptor's response to GABA (Gunner et al., 2023). This modulation occurs at both synaptic receptors, which mediate phasic inhibition, and extrasynaptic receptors, which mediate tonic inhibition; the latter are particularly sensitive to neurosteroid concentrations (Zorumski et al., 2019). Dysregulation of this neurosteroid-GABAergic signaling is a key factor in the pathophysiology of various neuropsychiatric conditions, including postpartum depression, major depressive disorder, and epilepsy (Zorumski et al., 2019). Therapeutic agents such as brexanolone and zuranolone act as positive allosteric modulators (PAMs) of these receptors, providing rapid-onset antidepressant effects by restoring inhibitory balance (FDA, 2019; FDA, 2023). However, the potent CNS-depressant effects of these drugs require careful monitoring for safety concerns such as excessive sedation and sudden loss of consciousness (FDA, 2019).

Other names

GABA(A) receptorNeurosteroid-sensitive GABA receptorGABA-A receptor complexLigand-gated chloride channelGABA-alpha receptor

Positive allosteric modulation (PAM) of the GABA-A receptor, which increases the frequency and/or duration of chloride ion channel opening in response to GABA, leading to neuronal hyperpolarization (Gunner et al., 2023; FDA, 2019).