Nicotinic acetylcholine receptor alpha 7 regulates cAMP signal within lipid rafts

Neuronal nicotinic acetylcholine receptors (nAChRs) are made of multiple subunits with diversified functions. The nAChR alpha 7-subunit has a property of high Ca2+ permeability and may have specific functions and localization within the plasma membrane as a signal transduction molecule. In PC-12 cel...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2003-09, Vol.285 (3), p.C567-C574
Main Authors: Oshikawa, Jin, Toya, Yoshiyuki, Fujita, Takayuki, Egawa, Masato, Kawabe, Junichi, Umemura, Satoshi, Ishikawa, Yoshihiro
Format: Article
Language:English
Subjects:
Adenylyl Cyclases - metabolism
alpha7 Nicotinic Acetylcholine Receptor
Animals
Cholesterol - metabolism
Cyclic AMP - metabolism
Membrane Microdomains - metabolism
Nicotine - pharmacology
Nicotinic Agonists - pharmacology
PC12 Cells
Rats
Receptors, Nicotinic - metabolism
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Summary:Neuronal nicotinic acetylcholine receptors (nAChRs) are made of multiple subunits with diversified functions. The nAChR alpha 7-subunit has a property of high Ca2+ permeability and may have specific functions and localization within the plasma membrane as a signal transduction molecule. In PC-12 cells, fractionation by sucrose gradient centrifugation revealed that nAChR alpha 7 existed in low-density, cholesterol-enriched plasma membrane microdomains known as lipid rafts where flotillin also exists. In contrast, nAChR alpha 5- and beta2-subunits were located in high-density fractions, out of the lipid rafts. Type 6 adenylyl cyclase (AC6), a calcium-inhibitable isoform, was also found in lipid rafts and was coimmunoprecipitated with nAChR alpha 7. Cholesterol depletion from plasma membranes with methyl-beta-cyclodextrin redistributed nAChR alpha 7 and AC6 diffusely within plasma membranes. Nicotine stimulation reduced forskolin-stimulated AC activity by 35%, and this inhibition was negated by either treatment with alpha-bungarotoxin, a specific antagonist of nAChR alpha 7, or cholesterol depletion from plasma membranes. The effect of cholesterol depletion was negated by the addition of cholesterol. These data suggest that nAChR alpha 7 has a specific membrane localization relative to other nAChR subunits and that lipid rafts are necessary to localize nAChR alpha 7 with AC within plasma membranes. In addition, nAChR alpha 7 may regulate the AC activity via Ca2+ within lipid rafts.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00422.2002