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Differential desensitization properties of rat neuronal nicotinic acetylcholine receptor subunit combinations expressed in Xenopus laevis oocytes


Differential desensitization properties of rat neuronal nicotinic acetylcholine receptor subunit combinations expressed in Xenopus laevis oocytes



Cellular and Molecular Neurobiology 15(4): 411-425



ISSN/ISBN: 0272-4340

PMID: 8565045

DOI: 10.1007/bf02071877

1. Chronic administration of nicotine up-regulates mammalian neuronal nicotinic acetylcholine receptors (nAChRs). A key hypothesis that explains up-regulation assumes that nicotine induces desensitization of receptor function. This is correlated with behaviorally expressed tolerance to the drug. 2. The present experiments were conducted to: (a) obtain information on the nicotine-induced desensitization of neuronal nAChR function, a less understood phenomenon as compared to that of the muscle and electric fish receptor counterparts; (b) test the hypothesis that different receptor subunit combinations exhibit distinct desensitization patterns. 3. Xenopus laevis oocytes were injected with mRNAs encoding rat receptor subunits alpha 2, alpha 3, or alpha 4 in pairwise combination with the beta 2 subunit. The responses to various concentrations of acetylcholine (ACh) or nicotine were analyzed by the two electrode voltage clamp technique. 4. Concentration-effect curves showed that nicotine was more potent than ACh for all the receptor subunit combinations tested. Only the alpha 4 beta 2 combination exhibited a depression of the maximum effect at concentrations higher than 20 microM nicotine. 5. After a single nicotine pulse, receptor desensitization (calculated as a single exponential decay) was significantly slower for alpha 4 beta 2 than for either alpha 3 beta 2 or alpha 2 beta 2. 6. Concentrations of nicotine that attained a near maximum effect were applied, washed, and re-applied in four minute cycles. The responses were calculated as percentages of the current evoked by the initial application. Following 16 minutes of this protocol, the alpha 4 beta 2 combination showed a greater reduction of the original response as compared to the alpha 2 beta 2 and alpha 3 beta 2 subunit combinations. Taking points 5 and 6 together, these experiments suggest that the alpha 4 beta 2 receptor subtype desensitizes at a slower rate and remains longer in the desensitized state. 7. Because alpha 4 beta 2 is the main receptor subunit combination within the brain and is up-regulated by nicotine, our data may be important for understanding the molecular basis of tolerance to this drug.

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Accession: 008469911

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