**12. GABA receptor classification and structure**

GABA receptors respond to the ligand GABA, which is the main inhibitory neurotransmit‐ ter in the mammalian central nervous system. GABAergic neurons are therefore important for modulating neuronal activity throughout the brain and spinal cord [63–70]. The enzyme L‐glutamic acid decarboxylase (GAD) synthesizes GABA in presynaptic terminals through the conversion of glutamate to GABA. GABA is then stored in vesicles waiting for release following neuronal activation [67]. Extracellular GABA can bind to either postsynaptic or extrasynaptic receptors located on presynaptic neurons, leading to hyperpolarization of the target cell [69]. Postsynaptic receptor activation mediates phasic inhibition, whereas extrasyn‐ aptic activation mediates a tonic inhibitory state [65, 69]. To remove extracellular GABA in the synaptic cleft, GABA transporters located on the presynaptic terminal and glial cells regulate neurotransmitter uptake; this process is extremely important to retain a balanced circuitry and prevent over inhibition [67].

GABA receptors are classified into two groups, GABAA and GABAB, with GABAC receptors recently categorized as a subtype of GABAA rather than their own distinct class. Receptor characterization is based on structural, biochemical, modulatory, and physiological differ‐ ences [67–70].

GABAA receptors are ionotropic chloride channels, conducting fast inhibitory neurotransmis‐ sion, in which a ligand (i.e., GABA) binds and directly induces pore opening [67, 69]. GABAA receptors are members of a much larger group referred to as the Cys‐loop ligand‐gated ion channel superfamily, which also encompasses nicotinic acetylcholine receptors (nAChRs), glycine receptors, and 5‐hydroxytryptamine type‐3 (5‐HT3 ) receptors [65, 68–70]. The diverse pharmacology displayed by GABAA receptors sets them apart from the rest of the family and is clinically relevant targets for anticonvulsant, anxiolytic, and sedative drugs [65, 69]. Typically, GABAA receptors are heteropentameric structures composed of five different sub‐ units (α1‐6, β1‐3, Υ1‐3 (Υ2S, Υ2L), ρ1‐3, δ, ε, θ, and π), each containing four transmembrane domains (TM1‐4) (**Figures 5** and **6**). Five out of twenty‐one available subunits comprise the complex, forming a pore from the TM2 segments [67–70]. The top three most common struc‐ tural compositions in the brain are α1β2γ2, α2β3γ2, and α3β3γ2, with the likely stoichiometry of 2α:2β:1γ [65, 67, 69].

Benzodiazepines potentiate the inhibitory effects of GABA by allosterically altering the receptor and increasing its affinity for GABA [67]. Benzodiazepine‐insensitive receptors are formed when the γ subunit is replaced by δ, ε, or π [69]. Rho (ρ) subunits are unique because these subunits predominately co‐assemble together to form homo‐ and hetero‐oligomers. Previously, ρ oligomers were classified as GABAC receptors, but more recently are consid‐ ered a subclass of GABAA receptors. Even though GABAA and GABAC receptors are structur‐ ally very similar to one another, these receptors formally fell into two different groups based on their differential pharmacology and physiology [69, 70]. A major difference between the A and C subtypes are that GABAA receptors are selectively blocked by bicuculline and modu‐ lated by benzodiazepines, steroids, and barbiturates. GABAC receptors are not sensitive to the same drugs, but rather are blocked by 1,2,5,6‐tetrahydropyridin‐4‐yl) methylphosphinic

**12. GABA receptor classification and structure**

glycine receptors, and 5‐hydroxytryptamine type‐3 (5‐HT3

and prevent over inhibition [67].

12 Schizophrenia Treatment - The New Facets

ences [67–70].

of 2α:2β:1γ [65, 67, 69].

GABA receptors respond to the ligand GABA, which is the main inhibitory neurotransmit‐ ter in the mammalian central nervous system. GABAergic neurons are therefore important for modulating neuronal activity throughout the brain and spinal cord [63–70]. The enzyme L‐glutamic acid decarboxylase (GAD) synthesizes GABA in presynaptic terminals through the conversion of glutamate to GABA. GABA is then stored in vesicles waiting for release following neuronal activation [67]. Extracellular GABA can bind to either postsynaptic or extrasynaptic receptors located on presynaptic neurons, leading to hyperpolarization of the target cell [69]. Postsynaptic receptor activation mediates phasic inhibition, whereas extrasyn‐ aptic activation mediates a tonic inhibitory state [65, 69]. To remove extracellular GABA in the synaptic cleft, GABA transporters located on the presynaptic terminal and glial cells regulate neurotransmitter uptake; this process is extremely important to retain a balanced circuitry

GABA receptors are classified into two groups, GABAA and GABAB, with GABAC receptors recently categorized as a subtype of GABAA rather than their own distinct class. Receptor characterization is based on structural, biochemical, modulatory, and physiological differ‐

GABAA receptors are ionotropic chloride channels, conducting fast inhibitory neurotransmis‐ sion, in which a ligand (i.e., GABA) binds and directly induces pore opening [67, 69]. GABAA receptors are members of a much larger group referred to as the Cys‐loop ligand‐gated ion channel superfamily, which also encompasses nicotinic acetylcholine receptors (nAChRs),

pharmacology displayed by GABAA receptors sets them apart from the rest of the family and is clinically relevant targets for anticonvulsant, anxiolytic, and sedative drugs [65, 69]. Typically, GABAA receptors are heteropentameric structures composed of five different sub‐ units (α1‐6, β1‐3, Υ1‐3 (Υ2S, Υ2L), ρ1‐3, δ, ε, θ, and π), each containing four transmembrane domains (TM1‐4) (**Figures 5** and **6**). Five out of twenty‐one available subunits comprise the complex, forming a pore from the TM2 segments [67–70]. The top three most common struc‐ tural compositions in the brain are α1β2γ2, α2β3γ2, and α3β3γ2, with the likely stoichiometry

Benzodiazepines potentiate the inhibitory effects of GABA by allosterically altering the receptor and increasing its affinity for GABA [67]. Benzodiazepine‐insensitive receptors are formed when the γ subunit is replaced by δ, ε, or π [69]. Rho (ρ) subunits are unique because these subunits predominately co‐assemble together to form homo‐ and hetero‐oligomers. Previously, ρ oligomers were classified as GABAC receptors, but more recently are consid‐ ered a subclass of GABAA receptors. Even though GABAA and GABAC receptors are structur‐ ally very similar to one another, these receptors formally fell into two different groups based on their differential pharmacology and physiology [69, 70]. A major difference between the A and C subtypes are that GABAA receptors are selectively blocked by bicuculline and modu‐ lated by benzodiazepines, steroids, and barbiturates. GABAC receptors are not sensitive to the same drugs, but rather are blocked by 1,2,5,6‐tetrahydropyridin‐4‐yl) methylphosphinic

) receptors [65, 68–70]. The diverse

**Figure 5.** GABAA receptor structure and cross‐section. GABAA receptors contain five subunits, typically in the ratio of 2α:2β:1γ, with the transmembrane domain 2 (TM2) forming the chloride‐permeable pore. Each subunit consists of four hydrophobic transmembrane domains with the N‐ and C‐ terminus facing the extracellular side. The GABA binding site is located at the interface between α and β subunit, while the benzodiazepine (BZs) binding site sits at the junction between α and γ. GABA binding triggers channel opening, allowing inward chloride ion flux, whereas benzodiazepine binding potentiates the GABA‐induced chloride influx [65, 69] (Modified from Jacob et al. [65] and Vithlani et al. [69]*).*

acid (TPMPA) and activated by Z‐4‐amniobut‐2‐enoic acid [cis‐aminocrotonic acid (CACA)]. Additionally, GABAC receptors exhibit a higher sensitivity to GABA, conduct less current, have longer channel opening times, and desensitize slower in the presence of an agonist. GABAC receptors, however, are no longer classified as a separate division, but are now con‐ sidered a GABAA‐ρ subclass because they are exclusively constructed of ρ subunits [70].

GABAB receptors are metabotropic Ca2+ or K+ channels, conducting slow inhibitory neu‐ rotransmission, in which a ligand (i.e., GABA) binds and indirectly induces pore opening through G‐protein coupling activation and second messenger signaling [64, 67, 68] (**Figure 7**). Functional GABAB receptors exist as heterodimers composed of one GABAB(1) (1a‐g) and one GABAB subunit [70]. The GABAB(1) subunit binds to GABA and is mandatory for functional receptors, whereas the GABAB2 subunit is responsible for G‐protein coupling and signaling. The most prevalent GABAB isoforms are GABAB(1a) and GABAB(1b), which are highly conserved across species. Other isoforms, 1c‐g, have also been identified, but are either species‐specific or do not exist naturally [64]. Baclofen, clinically used as a muscle relaxant, stimulates GABAB receptors, which are otherwise insensitive to drugs that modulate the GABAA receptors [67].

**Figure 6.** GABAA receptor transmembrane topology. Each subunit consists of four transmembrane domains. The N‐ and C‐terminus lie on the extracellular side, with the N‐terminus being the site of action for several drugs. A large intracellular domain exists between TM3 and TM4, providing a hub for a majority of the protein‐protein interactions as well as posttranslational modifications (palmitoylation, ubiquitination, phosphorylation) [65, 69].

**Figure 7.** GABAB receptor structure. GABAB receptors are heterodimers composed of either a 1a or 1b subunit and a mandatory 2 subunit. GABAB receptors are G‐protein coupled and are activated by the ligand GABA, which binds to the 1 subunit. Following GABA ligand binding, G‐protein activation induces opening of postsynaptic potassium channels and closing of presynaptic calcium channels, hyperpolarizing the target cell (Modified from Emson [64]).
