اهش گلوتامات با نیکوتین فعالیت ناقل نوع ۳
abstract
Nicotine, the main ingredient of tobacco, elicits seizures in animal models and cigarette smoking is regarded as a behavioral risk factor associated with epilepsy or seizures. In the hippocampus,the origin of nicotine-induced seizures, most glutamate uptake could be performed primarily by excitatory amino acid transporter type 3 (EAAT3). An association between temporal lobe epilepsy and EAAT3 downregulation has beenreported. Therefore, wehypothesizedthatnicotinemay elicit seizures throughthe attenuationof EAAT3 activity. We investigated chronic nicotine exposure (72 h) cause reduction of the activity of EAAT3 in a Xenopus oocyte expression system using a two-electrode voltage clamp. The roles of protein kinase C (PKC) andphosphatidylinositol 3-kinase (PI3K) were alsodetermined. Nicotine (0.001–1 M) resultedina time- and dose-dependent decrease in EAAT3 activity with maximal inhibition at nicotine concentrations of 0.03 M or higher and at an exposure time of 72 h. Vmax on the glutamate response was significantly reduced in the nicotine group (0.03 M for 72 h), but the Km value of EAAT3 for glutamate was not altered. When nicotine-exposed oocytes (0.03 M for 72 h) were pretreated with phorbol-12-myristate13-acetate (PMA, a PKC activator), the nicotine-induced reduction in EAAT3 activity was abolished. PKC inhibitors (staurosporine, chelerythrine, and calphostin C) significantly reduced basal EAAT3 activity, but there were no significant differences among the PKC inhibitors, nicotine, and PKC inhibitors + nicotine groups. Similar response patterns were observed among PI3K inhibitors (wortmannin and LY294002), nicotine, and PI3K inhibitors + nicotine. In conclusion, this study suggests that nicotine decreases EAAT3 activity, and that this inhibition seems to be dependent on PKC and PI3K. Our results may provide an additional mechanism for nicotine-induced seizure.
1. Introduction
Tobacco is a popular product world-wide despite the fact that nicotine causes toxicity and dependency. Pharmacologically, nicotine (methylpyridylpyrrolidine) is a water-soluble liquid alkaloid (Lavoie and Harris, 1991) which causes diverse central nervous system (CNS) effects, ranging from reduction of anxiety to seizure and coma (Picciotto et al., 2002). Smoking is regarded as a behavioral risk factor associated with epilepsy or seizure in epidemiological studies. People with epilepsy were found to smoke cigarettes more often than those without epilepsy (38.8% vs. 24.9%) (Kobau et al., 2004). In addition, participants reporting current cigarette smoking have an increased risk of seizure in comparison with those who never smoke (relative risk 2.60, 95% confidence interval 1.53–4.42) (Dworetzky et al., 2010). Moreover, accidental nicotine ingestion has been shown to cause seizures in children and adults (Lavoie and Harris, 1991; Smolinske et al., 1988).
چکیده
1- مقدمه
2- روندهای آزمایشگاهی
1-2- تهیه خمک
2-2- بیان EAAT3
3-2- ثبت الکتروفیزیولوژیک
4-2- مواد شیمایی
5-2- تیمار مواد شیمیایی آزمایشگاهی
6-2- آنالیز آماری
3- نتایج
4- بحث
ناسازگاری با بیان‌های مرتبط
abstract
1. Introduction
2. Experimental procedures
2.1. Oocyte preparation
2.2. Expression of EAAT3
2.3. Electrophysiological recording
2.4. Chemicals
2.5. Experimental chemical treatment
2.6. Statistical analysis
4. Discussion
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