Gamma-aminobutyric acid type A receptor subunit alpha-5 (GABRA5) (GABRA5)

The Gamma-aminobutyric acid type A (GABA-A) receptor containing the alpha-5 subunit is a pentameric ligand-gated ion channel primarily localized in the hippocampus and cerebral cortex [1, 3]. Unlike other GABA-A receptor subtypes that mediate phasic inhibition, alpha-5-containing receptors are predominantly extrasynaptic and provide tonic inhibition, which sets the threshold for neuronal firing and regulates network excitability [3, 4]. This receptor plays a pivotal role in cognitive functions, specifically learning and memory, by modulating long-term potentiation at synapses [1, 3]. Dysfunction or altered expression of the alpha-5 subunit is linked to several central nervous system disorders, including Alzheimer's disease, Down syndrome, schizophrenia, and major depressive disorder [2, 4]. Pharmacologically, negative allosteric modulators (NAMs) of this receptor are being developed as cognitive enhancers to improve memory performance without the pro-convulsant effects of non-selective GABA antagonists [3, 5]. Conversely, positive allosteric modulators (PAMs) are being investigated for their potential to treat mood disorders and chronic pain [4]. Because of its restricted expression in the brain, targeting the alpha-5 subunit offers a strategy to achieve therapeutic effects with reduced sedative and ataxic side effects compared to non-selective benzodiazepines [3, 4].

Other names

GABA-A receptor alpha-5 subunitGABRA5Alpha-5 subunit-containing GABA-A receptorGABA(A) receptor subunit alpha-5

Negative allosteric modulation (NAM) to reduce tonic inhibition and enhance synaptic plasticity; Positive allosteric modulation (PAM) to increase inhibitory tone for antidepressant or anxiolytic effects.