Forty Years Searching for Neurosteroid Binding Sites on GABAA Receptors

• Published in: Neuroscience 2024-06
• Main Authors: Mortensen, Martin, Bright, Damian P., Fagotti, Juliane, Dorovykh, Valentina, Cerna, Barbora, Smart, Trevor G.
• Format: Article
• Language: English
• Subjects: GABAA receptor structure; GABAA receptors; neurosteroid binding sites; neurosteroids
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2024.06.002

•Neurosteroids are modulators of GABAA receptors.•Neurosteroids can potentiate, directly activate, and inhibit GABAAR function.•This review charts the exploration of neurosteroid binding sites on GABAARs. Brain inhibition is a vital process for controlling and sculpting the excitability of the central nervous system in healthy individuals. This level of control is provided over several timescales and involves the neurotransmitter GABA acting at inhibitory synapses to: rapidly inhibit neurons by activating the GABAA receptor; over a slower timescale, to tonically activate extrasynaptic GABAA receptors to provide a low level of background inhibition; and finally, to activate G-protein coupled GABAB receptors to control transmitter release by inhibiting presynaptic Ca2+ channels whilst providing postsynaptic inhibition via K+ channel activation. From this plethora of roles for GABA and its receptors, the GABAA receptor isoform is of major interest due to its dynamic functional plasticity, which in part, is due to being targeted by modulatory brain neurosteroids derived from sex and stress hormones. This family of neurosteroids can, depending on their structure, potentiate, activate and also inhibit the activity of GABAA receptors to affect brain inhibition. This review tracks the methods that have been deployed in probing GABAA receptors, and charts the sterling efforts made by several groups to locate the key neurosteroid binding sites that affect these important receptors. Increasing our knowledge of these binding sites will greatly facilitate our understanding of the physiological roles of neurosteroids and will help to advance their use as novel therapeutics to combat debilitating brain diseases.