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  • Receptors containing an x y subunit interface where

    2023-09-27

    Receptors containing an αx/γy subunit interface, where x=1, 2, 3, 5 and y=1–3, form a high-affinity binding site for benzodiazepines (Figure 1A), for the later developed Z-drugs of different chemotypes, and for a large number of chemically distinct research compounds 17, 18 (Box 1 for examples). For receptors containing the γ1 or the γ3 subunits, the affinity and efficacy of many ligands are reduced 19, 20, 21. The α4 and α6 subunits provide a binding site for only a limited selection of compounds, and thus have traditionally been termed diazepam-insensitive (or DI) subunits to distinguish them from the diazepam-sensitive (DS) subunits [22]. Similarly, many of the less-abundant GABAA receptor isoforms do not bind benzodiazepines with high affinity ([11] for review). The majority of GABAA receptors are expressed in neuronal tissues, but the receptors are also found in many other organs. Therapeutic potential of receptors in airway smooth muscle to alleviate spasms in interleukins bronchialis is currently being explored 23, 24. However, we concentrate here on neuronal receptors. Synaptically located GABAA receptors, that are thought to mainly be composed of receptors assembled from two α, two β, and one γ subunit(s), mediate chloride ion currents at a single synapse that last for milliseconds. Another class, termed extrasynaptic receptors, mediate chloride currents lasting minutes and hours in large parts of the entire neuron, thereby adjusting excitability of the cell [25]. Although this review focuses on modulation of GABAA receptors by ligands of benzodiazepine binding sites, it should be pointed out that these receptors also respond to a wide variety of other modulators, including diverse toxins, barbiturates, intravenous anesthetics such as propofol and etomidate, volatile anesthetics such as isoflurane, neurosteroids, insecticides, and interleukins plant compounds (reviewed in [26]).
    The GABAA receptors belong to the family of cys-loop receptors. Insight into their atomic-level structure was provided by crystal structures of homologous proteins. First, the acetylcholine binding protein from lymnaea stagnalis[27] was analyzed, followed by pentameric ligand-gated channels from bacteria and C. elegans28, 29, 30. However, a high-resolution structure of the benzodiazepine binding site within the GABAA receptor is still missing. A human homomeric β3 GABAA receptor that lacks the intracellular domain has been crystallized [31], but unfortunately does not respond to either benzodiazepines or the natural agonist GABA. Owing to the high homology among subunits it is considered nevertheless to be a realistic model structure for the overall architecture of the binding site. All cys-loop receptor pentamers contain many cavities [32], whereby benzodiazepines have been shown to interact with multiple distinctive sites at extracellular and transmembrane localizations (Figure 1B).
    Classification of Benzodiazepine Binding Sites Historically, the sites at extracellular α+/γ− interfaces have been referred to as a single ‘high-affinity benzodiazepine binding site’, even though multiple GABAA receptor isoforms have such a site. This was justified because many ligands bind with very similar potency to most or all of these receptor isoforms. These high-affinity sites are formed by multiple discontinuous protein segments, termed ‘loops A–G’ [27] (Figure 1C). There are additional extracellular sites that are homologous to the canonical site (Figure 1B). The α+/β− interface is structurally similar to the α+/γ− interface. Therefore, it is of little surprise that some ligands of the high-affinity benzodiazepine site can also occupy this homologous subunit interface [33]. These compounds (e.g., CGS 8216; Box 1) can act as antagonists at the α/γ subunit interface and as positive allosteric modulators at the α/β subunit interface, or vice versa [34]. An additional high-affinity site for diazepam has recently been located in a homologous position at the β2+/γ2− subunit interface [35], which does not occur in αβγ receptors.