Forty Years Searching for Neurosteroid Binding Sites on GABA_A Receptors

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 GABA_A receptor; over a slower timescale, to tonically activate extrasynaptic GABA_A receptors to provide a low level of background inhibition; and finally, to activate G-protein coupled GABA_B 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 GABA_A 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 GABA_A receptors to affect brain inhibition. This review tracks the methods that have been deployed in probing GABA_A 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.