The influence of ␣ and  subunits on the properties of nicotineinduced activation and desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes was examined. Receptors containing ␣4 subunits were more sensitive to activation by nicotine than ␣3-containing receptors. At low concentrations of nicotine, nAChRs containing 2 subunits reached near-maximal desensitization more rapidly than 4-containing receptors. The concentration of nicotine producing half-maximal desensitization was influenced by the particular ␣ subunit expressed; similar to results for activation, ␣4-containing receptors were more sensitive to desensitizing levels of nicotine than ␣3-containing receptors. The ␣ subunit also influenced the rate of recovery from desensitization; this rate was approximately inversely proportional to the apparent nicotine affinity for the desensitized state. The homomeric ␣7 receptor showed the lowest sensitivity to nicotine for both activation and desensitization; ␣7 nAChRs also demonstrated the fastest desensitization kinetics. These subunitdependent properties remained in the presence of external calcium, although subtle, receptor subtype-specific effects on both the apparent affinities for activation and desensitization and the desensitization kinetics were noted. These data imply that the subunit composition of various nAChRs determines the degree to which receptors are desensitized and/or activated by tobacco-related levels of nicotine. The subtype-specific balance between receptor activation and desensitization should be considered important when the cellular and behavioral actions of nicotine are interpreted.
It is hypothesized that desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) induced by chronic exposure to nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing alpha4beta2 receptors were chronically incubated (24-48 hr) in nicotine, and the resulting changes in specific [3H]nicotine binding to surface receptors on intact oocytes were compared with functional receptor desensitization. Four lines of evidence strongly support the hypothesis. (1) The half-maximal nicotine concentration necessary to produce desensitization (9.7 nM) was the same as that needed to induce upregulation (9.9 nM). (2) The concentration of [3H]nicotine for half-maximal binding to surface nAChRs on intact oocytes was also similar (11.1 nM), as predicted from cyclical desensitization models. (3) Functional desensitization of alpha3beta4 receptors required 10-fold higher nicotine concentrations, and this was mirrored by a 10-fold shift in concentrations necessary for upregulation. (4) Mutant alpha4beta2 receptors that do not recover fully from desensitization, but not wild-type channels, were upregulated after acute (1 hr) applications of nicotine. Interestingly, the nicotine concentration required for half-maximal binding of alpha4beta2 receptors in total cell membrane homogenates was 20-fold lower than that measured for surface nAChRs in intact oocytes. These data suggest that cell homogenate binding assays may not accurately reflect the in vivo desensitization affinity of surface nAChRs and may account for some of the previously reported differences in the efficacy of nicotine for inducing nAChR desensitization and upregulation.
FENSTER, CATHERINE P., ROLAND L. WEINSIER, VICTOR M. DARLEY-USMAR, AND RAKESH P. PATEL. Obesity, aerobic exercise, and vascular disease: the role of oxidant stress. Obes Res. 2002;10:964 -968. Oxidant formation in the vasculature contributes to vascular disease and dysfunction associated with obesity. In contrast, exercise-dependent production of oxidants may stimulate adaptive responses that protect against the development of such diseases. In this review, we discuss current concepts in the biology of reactive oxygen and nitrogen species and how their function is modulated in the context of vascular disease, obesity, and aerobic exercise.
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