Chronic Nicotine Treatment Up-Regulates α3 and α7 Acetylcholine Receptor Subtypes Expressed by the Human Neuroblastoma Cell Line SH-SY5Y

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Abstract
Chronic exposure to nicotine has been reported to increase the number of nicotinic acetylcholine receptors (AChRs) in brain. The mechanism of up-regulation for the α4β2 AChR subtype, which accounts for the majority of high affinity nicotine binding in mammalian brain, has previously been shown to involve a decrease in the rate of α4β2 AChR turnover. Here, we report an investigation of the extent and mechanism of nicotine-induced up-regulation of α3 AChRs and α7 AChR subtypes expressed in the human neuroblastoma cell line SH-SY5Y. Up-regulation of human α3 AChRs and α7 AChRs, unlike α4β2 AChRs, requires much higher nicotine concentrations than are encountered in smokers; the extent of increase of surface AChRs is much less; and the mechanisms of up-regulation are different than with α4β2 AChRs. The mechanisms of up-regulation may be different for α3 AChRs or α7 AChRs. Chronic treatment with nicotine or carbamylcholine, but not d-tubocurarine, mecamylamine, or dihydro-β-erythroidine, induced a 500–600% increase in the number of α3 AChRs but only a 30% increase in α7 AChRs. Chronic nicotine treatment did not increase affinity for nicotine or increase the amount of RNA for α3 or α7 subunits. The effect of nicotine on up-regulation of α7 AChRs was partially blocked by either d-tubocurarine or mecamylamine. The effect of nicotine treatment on the number of α3 AChRs was only slightly blocked by the antagonistsd-tubocurarine, mecamylamine, or dihydro-β-erythroidine at concentrations that efficiently block α3 AChR function. Most of the nicotine-induced increase in α3 AChRs was found to be intracellular. The α3 AChRs, which accumulate intracellularly, were shown to have been previously exposed on the cell surface by their susceptibility to antigenic modulation. The data suggest that chronic exposure to nicotine may induce a conformation of cell surface α3 AChRs that at least in this cell line are consequently internalized but not immediately destroyed.