Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system (CNS). It plays a crucial role in regulating neuronal excitability throughout the nervous system. GABA exerts its effects through two main types of receptors: GABA(A) and GABA(B) receptors. Among these, GABA(A) receptors are the most prominent and are ligand-gated ion channels that mediate fast synaptic inhibition.
GABA(A) receptors are heteropentameric complexes composed of various subunits. There are 19 known subunits that can combine to form these receptors: six α (alpha1-6), three β (beta1-3), three γ (gamma1-3), three ρ (rho1-3), and one each of the δ (delta), ε (epsilon), π (pi), and θ (theta) subunits . The most common configuration in the human brain consists of two α subunits, two β subunits, and one γ subunit arranged in a specific manner around a central chloride ion channel .
GABA(A) Receptor-Associated Protein (GABARAP) is a protein that plays a critical role in the trafficking and function of GABA(A) receptors. It is encoded by the GABARAP gene in the human genome . GABARAP is involved in the intracellular transport of GABA(A) receptors to the cell membrane, where they can participate in synaptic transmission. This protein is essential for the proper localization and function of GABA(A) receptors, thereby influencing inhibitory neurotransmission in the CNS.
The proper functioning of GABA(A) receptors is vital for maintaining the balance between excitation and inhibition in the brain. Dysregulation of GABAergic signaling has been implicated in various neurological and psychiatric disorders, including epilepsy, anxiety, insomnia, and schizophrenia . GABARAP, by ensuring the correct trafficking and localization of GABA(A) receptors, plays a crucial role in maintaining this balance and, consequently, normal brain function.
Given the importance of GABA(A) receptors in various CNS disorders, GABARAP has emerged as a potential therapeutic target. Modulating the function or expression of GABARAP could influence the availability and activity of GABA(A) receptors, offering new avenues for the treatment of conditions associated with GABAergic dysfunction . Research is ongoing to develop compounds that can specifically target GABARAP and modulate its activity for therapeutic benefit.