Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor

Atomic Force Microscopy Reveals the Stoichiometry and Subunit Arrangement of the α4β3δ GABAAReceptor

“…According to the sequence database, the ␣ 4 -subunit has three consensus glycosylation sites. Mapping the sequence of the ␣ 4 -subunit onto a model of the structure of the ␣ 1 ␤ 2 ␥ 2 form of receptor (Mokrab et al, 2007) indicates that these sites are 0.7, 2.6, and 4.7 nm from the most extracellular part of the protein. The ␤ 3 -subunit also has three consensus glycosylation sites, which are 1.4, 1.6, and 7.0 nm from the most extracellular part of the receptor.…”

“…However, because the predominant forms of the two receptor subtypes have the same subunit stoichiometry and arrangement, it must be their unique subunit compositions that underlie their distinct GABA activation properties. Understanding of the molecular determinants of the recognition and functional characteristics of the "classic" GABA A receptor, ␣ 1 ␤ 2 ␥ 2 , has benefited significantly from the development of comparative homology models (Ernst et al, 2005;Mokrab et al, 2007). The elucidation of the subunit arrangement in the ␣ 4 ␤ 3 ␦ subtype provides an opportunity to develop similar models for this receptor subtype, the importance of which in the control of neuronal excitability is becoming increasingly recognized (Farrant and Nusser, 2005).…”

“…Thus, although the ␦-containing receptors represent only a minor component of the total GABA A receptor population, their atypical properties render them attractive novel targets for drug development. Exploration of receptor attributes at the molecular level has been facilitated by the construction of homology models of the ␣ 1 ␤ 2 ␥ 2 receptor, using the nicotinic acetylcholine receptor as the structural template (Ernst et al, 2005;Mokrab et al, 2007). However, because recognition sites for agonists, antagonists, and allosteric agents are found at subunit interfaces within this family, it is important to determine not only the stoichiometry but also the architecture of the subunits within the pentamer if useful homology models are to be constructed for other receptor subtypes.…”

Synthesis and anticonvulsant activity of a new 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine

“…Among these, 10 compounds (2b-d, 2h and 2m-r) were more active than the leading compound V in the MES test, and four compounds (2o-r) had lower neurotoxicity than the leading compound V. The remaining eight compounds (2a, 2e-g and 2i-l) did not show activity even at 100 mg/kg. We believe that the higher anticonvulsant activity of some compounds may be due to the triazole ring, which enhanced higher affinity of the pyridazine ring for the recognition site [14].…”

“…The hypothesis was that a triazole ring may have higher affinity for the receptor and enhance anticonvulsant activity, and there were some similar design reports [12,13]. Chau et al [14]. carried out a similar docking experiment with the imidazobenzodiazepine, alprazolam.…”