. Structure of a human synaptic GABAA receptor. Nature. 2018 Jun 27; PubMed.

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  1. GABAA receptors, among the most predominant inhibitory receptors in the central nervous system, constitute heteromeric structures formed by the assembly of five subunits, the most common of which are α, β, γ, δ. These subunits host a number of binding sites for endogenous or synthetic modulators.

    This work is an outstanding collection of data on the synaptic isoform of the human GABAA receptor. It sheds light into mechanisms by which the GABA neurotransmitter or endogenous modulators, neurosteroids (e.g., allopregnanolone) with selectivity for the β-α subunit interface, act on GABAA receptors.

    Understanding the receptor architecture of GABAA receptors is pivotal not only to predict dysfunction of its homonymous neurotransmitter, GABA, but also for that of other endogenous modulators, including neurosteroids. Knowledge of its structure is also important to anticipate lack of pharmacological action of a number of other synthetic agents, including benzodiazepines, barbiturates, and anesthetics, and even alcohol.

    Through their binding sites on the GABAA receptors, neurosteroids potentiate the action of GABA and play a neurophysiological role of fine-tuning of the receptor for synthetic modulators, including benzodiazepines and barbituates. Furthermore, neurosteroids, by regulating GABAA receptor strength, regulate emotional behaviors such as expression of aggression and impulsivity, anxiety, and fear. Hence, it is not surprising that this receptor is involved in neurological and psychiatric disorders that range from anxiety spectrum disorders to autism and from drug addiction to epilepsy and post-traumatic stress disorder (PTSD).  

    Both subunit expression and assembly of GABAA receptors, as well as the biosynthesis of GABA and neurosteroids, are highly susceptible to environmental factors, including stress and pharmacological treatment. Stress per se may change the expression of subunits such that the receptor becomes insensitive to the pharmacological action of benzodiazepines. For example, stress-induced changes in the neurobiology of PTSD result in a GABAA receptor conformation with reduced benzodiazepine binding sites. Indeed, benzodiazepines such as Xanax, which improve symptoms in anxiety disorders and panic, fail to help PTSD patients. Likewise, stress downregulates physiological levels of GABAergic neurosteroids, which results in decreased GABAergic neurotransmission and behavioral dysfunction.

    In Alzheimer’s disease, both animal models and evidence from postmortem human brain suggest a number of morphological and functional changes consistent with remodeling of GABAA receptors.

    For example, in AD brain areas, GABAA receptors were less sensitive to GABA, and GABAA receptor α1 and γ2 subunits were downregulated. Given that benzodiazepines bind at the interface of the α1-3,5/γ2, these changes are consistent with a lower efficacy of these anxiolytic drugs, which may prove unsuccessful in controlling behavioral changes in AD patients, including anxiety and impulsivity.

    Hence, the work presented by Zhu and colleagues will help us understand why current drugs fail to exert pharmacological properties, but most importantly, it will help anticipate future design of successful GABAA receptor agents for the treatment of neurological and psychiatric disorders.

    View all comments by Graziano Pinna

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  1. Courtesy of Cryo-EM: GABAA Receptor in Close-Up View