Lovastatin differentially regulates α7 and α4 neuronal nicotinic acetylcholine receptor levels in rat hippocampal neurons

Abstract

Abstract: Neuronal 7 and 4 2 are the predominant nicotinic acetylcholine receptor (nAChR) subtypes found in the brain, particularly in the hippocampus. The e ects 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 M range. Chronic (14 days) lovastatin treatment augmented cell-surface levels of 7 and 4 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 byWestern blots. At low lovastatin concentrations (10–100 nM), the increase in 4 nAChR in neurites was higher than in neuronal cell somata; the opposite occurred at higher (0.5–1 M) lovastatin concentrations. In contrast, neurite 7 nAChRs raised more than somatic 7 nAChRs at all lovastatin concentrations tested. These results indicate that cholesterol levels homeostatically regulate 7 and 4 nAChR levels in a di erential manner through mechanisms that depend on statin concentration and receptor localization. The neuroprotective pleomorphic e ects of statins may act by reestablishing the homeostatic equilibrium.