Molecular pharmacology
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Molecular pharmacology · Apr 2009
Comparative StudyAcetylcholine-stimulated [3H]GABA release from mouse brain synaptosomes is modulated by alpha4beta2 and alpha4alpha5beta2 nicotinic receptor subtypes.
Nicotinic acetylcholine receptor (nAChR) agonists stimulate the release of GABA from GABAergic nerve terminals, but the nAChR subtypes that mediate this effect have not been elucidated. The studies reported here used synaptosomes derived from the cortex, hippocampus, striatum, and thalamus of wild-type and alpha4-, alpha5-, alpha7-, beta2-, and beta4-null mutant mice to identify nAChR subtypes involved in acetylcholine (ACh)-evoked GABA release. Null mutation of genes encoding the alpha4 or beta2 subunits resulted in complete loss of ACh-stimulated [(3)H]GABA release in all four brain regions. ⋯ Moreover, a selective reduction in the maximum response of the high-affinity component was apparent in alpha5-null mutant mice. The results demonstrate that alpha4beta2-type nAChRs are critical for ACh-stimulated [(3)H]GABA release from all four brain regions examined. In addition, the results suggest that alpha5-containing receptors on GABAergic nerve terminals comprise a fraction of the high ACh-sensitivity component of the concentration-response curve and contribute directly to the ability of nicotinic agonists to evoke GABA release in these regions.
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Molecular pharmacology · Apr 2009
Comparative StudySteroid interaction with a single potentiating site is sufficient to modulate GABA-A receptor function.
Neuroactive steroids are efficacious potentiators of GABA-A receptors. Recent work has identified a site in the alpha1 subunit of the GABA-A receptor, that is essential for potentiation by steroids. However, each receptor contains two copies of the alpha1 subunit. ⋯ Mutation of only one alpha1 subunit does not produce the full effect of mutating both sites. Overall, the data demonstrate that at a macroscopic level, the presence of a single wild-type steroid-binding site is sufficient to mediate responses to steroid, but both must be mutated to completely remove the effects of steroids. Differences between the two sites seem to be relatively subtle.