Abstract
Neuronal α7 and α4β2 are the predominant nicotinic acetylcholine receptor (nAChR) subtypes found in the brain, particularly in the hippocampus. The effects of lovastatin, an inhibitor of cholesterol biosynthesis, on these two nAChRs endogenously expressed in rat hippocampal neuronal cells were evaluated in the 0.01–1 µM range. Chronic (14 days) lovastatin treatment augmented cell-surface levels of α7 and α4 nAChRs, as measured by fluorescence microscopy and radioactive ligand binding assays. This was accompanied in both cases by an increase in total protein receptor levels as determined by Western blots. At low lovastatin concentrations (10–100 nM), the increase in α4 nAChR in neurites was higher than in neuronal cell somata; the opposite occurred at higher (0.5–1 µM) lovastatin concentrations. In contrast, neurite α7 nAChRs raised more than somatic α7 nAChRs at all lovastatin concentrations tested. These results indicate that cholesterol levels homeostatically regulate α7 and α4 nAChR levels in a differential manner through mechanisms that depend on statin concentration and receptor localization. The neuroprotective pleomorphic effects of statins may act by reestablishing the homeostatic equilibrium.
Highlights
Nicotinic acetylcholine receptors are prototypic members of the pentameric ligand-gated ion channel superfamily [1]
We found that lovastatin treatment augments surface expression levels, as well as total expression of α7 and α4 nicotinic acetylcholine receptor (nAChR), and that these increases depend on the lovastatin dose and receptor membrane localization
In order to assess the effect of chronic lovastatin treatment on the distribution and levels of α7- and α4-containing nAChRs in neuronal cells, we incubated neurons in primary cultures with different lovastatin concentrations for up to 14 days
Summary
Nicotinic acetylcholine receptors (nAChR) are prototypic members of the pentameric ligand-gated ion channel (pLGIC) superfamily [1]. Upon binding to the nAChR, acetylcholine—the natural ligand—promotes the opening of this ion channel, formed by five polypeptide subunits organized pseudo-symmetrically around a central pore [2]. In the central nervous system, nAChRs are present as homomeric or heteromeric receptors. The most abundant homomeric nAChR species in the central nervous system is the α7 nAChR, whereas the majority of the heteromeric nAChRs result from the combination of α4 and β2 subunits [3]. The homomeric α7 subtype plays a crucial role in various cognitive functions, including learning and memory [4,5]. There is substantial experimental evidence supporting the notion that α7
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