Toxicology and applied pharmacology
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Toxicol. Appl. Pharmacol. · Feb 2011
GABAA receptor open-state conformation determines non-competitive antagonist binding.
The γ-aminobutyric acid (GABA) type A receptor (GABA(A)R) is one of the most important targets for insecticide action. The human recombinant β3 homomer is the best available model for this binding site and 4-n-[(3)H]propyl-4'-ethynylbicycloorthobenzoate ([(3)H]EBOB) is the preferred non-competitive antagonist (NCA) radioligand. The uniquely high sensitivity of the β3 homomer relative to the much-less-active but structurally very-similar β1 homomer provides an ideal comparison to elucidate structural and functional features important for NCA binding. ⋯ However, the binding activity of α1β1S15'N was insensitive to GABA and α1β3N15'S was stimulated much less than wildtype α1β3 by GABA. The inhibitory effect of etomidate on NCA binding was reduced more than 5-fold by the mutation β3N15'S. Therefore, the NCA binding site is tightly regulated by the open-state conformation that largely determines GABA(A) receptor sensitivity.
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Toxicol. Appl. Pharmacol. · Feb 2011
The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease.
Isoflurane is known to increase β-amyloid aggregation and neuronal damage. We hypothesized that isoflurane will have similar effects on the polyglutamine huntingtin protein and will cause alterations in intracellular calcium homeostasis. We tested this hypothesis in striatal cells from the expanded glutamine huntingtin knock-in mouse (STHdh(Q111/Q111)) and wild type (STHdh(Q7/Q7)) striatal neurons. ⋯ Xestospongin C inhibited the isoflurane-induced calcium release from the ER, aggregation of huntingtin, and cell damage in the STHdh(Q111/Q111) cells. In summary, the Q111 form of huntingtin increases the vulnerability of striatal neurons to isoflurane neurotoxicity through combined actions on the ER IP(3) receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdh(Q111/Q111) striatal cells.