European Journal of Pharmacology: Molecular Pharmacology
Regular paperNatural mutation of GABAA receptor α6 subunit alters benzodiazepine affinity but not allosteric GABA effects
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Biological behavior of 1, 4-benzodiazepines and 1, 4-benzothiazepines
2022, Benzodiazepine-Based Drug DiscoveryThe neurobiology of alcohol consumption and alcoholism: An integrative history
2013, Pharmacology Biochemistry and BehaviorCitation Excerpt :These rats have been selectively bred for many generations to demonstrate genetically determined differences in response to the incoordinating effects of ethanol (AT rats show little effect, ANT rats are highly sensitive Eriksson and Rossi, 1981). Esa Korpi and his colleagues (Malminen and Korpi, 1988; Uusi-Oukari and Korpi, 1989) discovered an interesting mutation (Korpi and Seeburg, 1993) in the α6 subunit that distinguished the AT from the ANT rats. This mutation in the α6 subunit in the ANT rats resulted in GABA-A receptors which were significantly more sensitive to benzodiazepines (Korpi and Seeburg, 1993), and significantly different in the characteristics for the binding of the purported (Suzdak et al., 1986a) “alcohol antagonist”, Ro-15-4513 (Uusi-Oukari and Korpi, 1990).
Hooked on benzodiazepines: GABA<inf>A</inf> receptor subtypes and addiction
2011, Trends in NeurosciencesDoes ethanol act preferentially via selected brain GABA<inf>A</inf> receptor subtypes? the current evidence is ambiguous
2007, AlcoholCitation Excerpt :The density of high-affinity [3H]muscimol binding sites is lower in cerebellar membranes of ANT rats than in those of AT rats (Mäkelä et al., 1996; Uusi-Oukari and Korpi, 1989), although there is no indication that these binding properties differ between the α6β2γ2 and α6(R100Q)β2γ2 receptors. The KD values of about 3 nM, that is, in the same range as for α1β2γ2 receptors (KD, 8 nM; Korpi and Seeburg, 1993). The high-affinity [3H]muscimol binding in the cerebellum is dependent on the expression of α6 and δ subunit-containing receptors (Korpi et al., 2002b).
Modulation of GABA<inf>A</inf> receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies
2007, AlcoholCitation Excerpt :It was subsequently shown that the binding difference was mediated by the α6-R100Q single nucleotide polymorphism (SNP) (Korpi et al., 1993; also see Korpi et al., this issue). It is likely that this point mutation accounts for at least part of the genetic difference in benzodiazepine sensitivity in the AT and ANT rats (Korpi and Seeburg, 1993). Given the known interaction between EtOH and GABAA-Rs, it has been speculated by many investigators that the α6-R100Q mutation might be at least partially responsible for the differential EtOH sensitivity of the AT and ANT selected lines, although in the original report it was noted that the mutation did not affect EtOH modulation of α6β2γ2 receptors expressed in a cell culture system (Korpi et al., 1993).