Dopamine transporter activity mediates amphetamine-induced inhibition of Akt through a Ca2+/calmodulin-dependent kinase II-dependent mechanism.

The primary mechanism for clearance of extracellular dopamine (DA) is uptake mediated by the dopamine transporter (DAT), which is governed, in part, by the number of functional DATs on the cell surface. Previous studies have shown that amphetamine (AMPH) decreases DAT cell surface expression, whereas insulin reverses this effect through the action of phosphatidylinositol 3-kinase (PI3K). Therefore, it is possible that AMPH causes DAT cell surface redistribution by inhibiting basal insulin signaling. Here, we show in a heterologous expression system and in murine striatal synaptosomes that AMPH causes a time-dependent decrease in the activity of Akt, a protein kinase immediately downstream of PI3K. This effect was blocked by the DAT inhibitor cocaine, suggesting that AMPH must interact with DAT to inhibit Akt. We also showed that AMPH is able to stimulate Ca2+/calmodulin-dependent kinase II (CaMKII) activity, both in the heterologous expression system as well as in murine striatal synaptosomes. The ability of AMPH to decrease Akt activity was blocked by the CaMKII inhibitor 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (KN93), but not by its inactive analog 2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (KN92). Furthermore, preincubation with KN93 prevented the AMPH-induced decrease in DAT cell surface expression. Thus, AMPH, but not cocaine, decreases Akt activity through a CaMKII-dependent pathway, thereby providing a novel mechanism by which AMPH regulates insulin signaling and DAT trafficking.

[Indoor radon pollution in houses in the Apulian Region of Italy and evaluation of the probability of lung cancer in the population]. / Contaminazione da radon indoor nelle abitazioni pugliesi e valutazione della probabilità di insorgenza di tumore polmonare nella popolazione residente.

BACKGROUND: Radon-222 is a gaseous radioactive chemical which can be transformed into other radioactive chemicals, defined as "products of decay" or "radon's daughter". The modality of radon penetration into the buildings depends on the convection motion created in the ground, which suck it back, so causing the penetration. The principal effect on human health is the increase risk of lung cancer, in proportion to the concentration and the time people spend indoors with exposure to radon. OBJECTIVES: The study proposed to estimate the expected cases of radon-induced lung cancer in the population of Apulia due to contamination by indoor radon. METHODS: The study used the data obtained in a national survey made by ANPA (National Environmental Protection Agency) and ISS (High Health Institute), with the collaboration of the Regional Reference Centres for the Control of Environmental Radioactivity (CRR). In the Apulia Region 310 families (5000 nationwide) were involved, which were selected so as to constitute a representative sample both of the region and the country. Appropriate instruments for the measurement of mean concentrations of indoor radon (passive nuclear trace monitors were installed in the homes of the sample families in two different periods of year). We evaluated the variations of indoor radon concentration in the houses during spring-summer and autumn-winter periods, observing a predictable increase in the latter period. We assessed concentrations in relation to: 1. architectural features and location, 2. construction year, 3. building material, 4. presence of windows. RESULTS: We found higher contamination in the oldest non-cement buildings and on the lower floors. In Lecce and Castrì di Lecce we found a mean radon concentration higher than the national and the regional mean, which is equivalent to annual exposure of 0.54 and 0.46 WLM respectively. For these levels we estimated that the expected cases of radon-induced lung cancer will be 1.5 in Lecce and 1.3 in Castrì per 10,000 inhabitants. CONCLUSION: The results of our investigations confirm that indoor radon pollution is a significant problem as it is one of the main causes of lung cancer. Hence, precautionary measures to reduce as much as possible exposure to indoor radon are highly recommended.