In this review we attempt to summarize experimental evidence on the existence of defined native GABA(A) receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge. This will serve to update the most recent classification of GABA(A) receptors (Pharmacol Rev 50:291-313, 1998) approved by the Nomenclature Committee of the International Union of Pharmacology. GABA(A) receptors are chloride channels that mediate the major form of fast inhibitory neurotransmission in the central nervous system. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share structural and functional homology with other members of that family. GABA(A) receptors are assembled from a family of 19 homologous subunit gene products and form numerous, mostly hetero-oligomeric, pentamers. Such receptor subtypes with properties that depend on subunit composition vary in topography and ontogeny, in cellular and subcellular localization, in their role in brain circuits and behaviors, in their mechanisms of regulation, and in their pharmacology. We propose several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a list of native hetero-oligomeric subtypes. With these criteria, we develop a working GABA(A) receptor list, which currently includes 26 members, but will undoubtedly be modified and grow as information expands. The list is divided into three categories of native receptor subtypes: "identified," "existence with high probability," and "tentative."

/pdf/international-union-of-pharmacology-lxx-subtypes-of-g-5euffgc9t5.pdf

International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update

https://www.cell.com/neuron/pdf/S0896-6273(11)01093-2.pdf

Extrasynaptic GABAA receptors: Their function in the CNS and implications for disease

The GABA system in anxiety and depression and its therapeutic potential.

Activation of GABAA Receptors: Views from Outside the Synaptic Cleft

The γ-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, α5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of α2- and α3-subunit-containing GABAA receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for ant...

GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism.

IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABAA receptors containing an 1, 2, 3, or 5 subunit but has inverse agonist efficacy selective for the 5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primar- ily via GABAA receptors containing an 5 subunit. In a mouse hippocampal slice model, 5IA significantly enhanced the burst-induced long-term potentiation of the excitatory postsyn- aptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data sug- gesting that 5IA may enhance cognition without being pro- convulsant were confirmed in in vivo rodent models. Hence, 5IA significantly enhanced performance in a rat hippocampal- dependent test of learning and memory, the delayed-matching- to-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice 5IA was not con- vulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, 5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABAA 5-subtype pro- vides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.

W. Rycroft

Papers

An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition