Lovastatin Differentially Regulates α7 and α4 Neuronal Nicotinic Acetylcholine Receptor Levels in Rat Hippocampal Neurons

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.

Dysregulation of Neuronal Nicotinic Acetylcholine Receptor–Cholesterol Crosstalk in Autism Spectrum Disorder

“…α7 nAChRs in cholesterol-rich liquid-ordered lipid domains (Brusés et al, 2001;Marchand et al, 2002;Oshikawa et al, 2003;Zhu et al, 2006), may constitute a non-activatable pool of nicotinic receptors, as suggested by Báez-Pagán and coworkers (Báez-Pagán et al, 2016). Long-term inhibition of cholesterol biosynthesis by the drug lovastatin differentially augments cell-surface levels of α4β2 and α7 nAChRs in neurites and soma of rat hippocampal neurons (Borroni et al, 2020). In conclusion, dysregulation of cholesterol homeostasis affects the stability, distribution and conductance of both muscle-type and neuronal nAChRs.…”

“…Brain cholinergic system dysfunction has also been reported in ASD (Hardan and Handen, 2002;Eissa et al, 2018). Since nAChR function is influenced by its lipid microenvironment (see reviews in Barrantes, 2004Barrantes, , 2017 and cell-surface trafficking of nAChRs is dependent on cholesterol metabolism (Pediconi et al, 2004;Borroni et al, 2020) we explore in this review the various neurological alterations described in ASD and their possible association with an abnormal crosstalk between nAChRs and cholesterol.…”

The Plasma Membrane as the Arena for Receptor-Receptor Crosstalk

“…The α7 nAChR subtype of nAChRs is predominantly located in cholesterol-rich Lo domains [117][118][119][120]. Other studies from our laboratory indicate that longterm inhibition of cholesterol biosynthesis can differentially augment cell-surface levels of both α4β2 and α7 nAChRs in neurites and soma of rat hippocampal neurons [121].…”

Nanoscale Sub-Compartmentalization of the Dendritic Spine Compartment

“…Changes in cholesterol levels alter the translational mobility of the receptor in the plane of the plasma membrane, as measured by fluorescence recovery after photobleaching and fluorescence correlation spectroscopy [ 165 ] and single-molecule localization microscopy [ 166 , 167 ]. Cell-surface trafficking of nAChRs is dependent on cholesterol metabolism [ 168 , 169 ]. Pharmacological long-term inhibition of cholesterol biosynthesis by the statin lovastatin differentially augments cell-surface levels of α4β2 and α7 nAChRs in neurites and soma of rat hippocampal neurons [ 169 ].…”

“…Cell-surface trafficking of nAChRs is dependent on cholesterol metabolism [ 168 , 169 ]. Pharmacological long-term inhibition of cholesterol biosynthesis by the statin lovastatin differentially augments cell-surface levels of α4β2 and α7 nAChRs in neurites and soma of rat hippocampal neurons [ 169 ]. Misbalances in brain cholesterol homeostasis affect cholinergic signaling involving α4β2 and α7 nAChRs and indirectly impact on the number and distribution of other neuroreceptors at dendritic spines, with important consequences for brain function.…”