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Barrio-Real L.,University of Salamanca | Barrueco M.,University of Salamanca | Gonzalez-Sarmiento R.,University of Salamanca | Caloca M.J.,Institute Biologia y Genetica Molecular IBGM
Journal of Investigative Medicine | Year: 2013

Objective: The CHN2 gene encodes the A2-chimaerin, a Rac-specific guanosine-5¶-triphosphatase activating protein with an important role in the establishment of functional brain circuitry by controlling axon pruning. Genetic studies suggest that the CHN2 gene harbors variants that contribute to addiction vulnerability and smoking behavior. To further evaluate the role of A2-chimaerin in nicotine addiction, we investigated the association of 3 individual polymorphisms of the CHN2 gene with smoking dependence. Methods: Three hundred sixty-one healthy volunteers, 173 smokers (mean T SD age, 60.4 T 1.4 years) and 188 control subjects (mean T SD age, 45.9 T 1.4 years) were genotyped for 3 single-nucleotide polymorphisms in the CHN2 gene (rs3750103, rs12112301, and rs186911567). The association of these polymorphisms with smoking habits was analyzed. Results: There was no significant association of polymorphisms rs12112301 and rs3750103 with smoking. However, there was a significant difference in the frequency of the rs186911567 polymorphism between the smokers and the controls (P = 0.003). Conclusions: We report for the first time a significant association of the novel rs186911567 polymorphism of the CHN2 gene with smoking. © 2013 by The American Federation for Medical Research. Source

Calvo M.,University of Valladolid | Sanz-Blasco S.,University of Valladolid | Caballero E.,University of Valladolid | Villalobos C.,University of Valladolid | And 2 more authors.
Journal of Neurochemistry | Year: 2015

Brain damage after insult and cognitive decline are related to excitotoxicity and strongly influenced by aging, yet mechanisms of aging-dependent susceptibility to excitotoxicity are poorly known. Several non-steroidal anti-inflammatory drugs (NSAIDs) may prevent excitotoxicity and cognitive decline in the elderly by an unknown mechanism. Interestingly, after several weeks in vitro, hippocampal neurons display important hallmarks of neuronal aging in vivo. Accordingly, rat hippocampal neurons cultured for several weeks were used to investigate mechanisms of aging-related susceptibility to excitotoxicity and neuroprotection by NSAIDs. We found that NMDA increased cytosolic Ca2+ concentration in young, mature and aged neurons but only promoted apoptosis in aged neurons. Resting Ca2+ levels and responses to NMDA increased with time in culture which correlated with changes in expression of NMDA receptor subunits. In addition, NMDA promoted mitochondrial Ca2+ uptake only in aged cultures. Consistently, specific inhibition of mitochondrial Ca2+ uptake decreased apoptosis. Finally, we found that a series of NSAIDs depolarized mitochondria and inhibited mitochondrial Ca2+ overload, thus preventing NMDA-induced apoptosis in aged cultures. We conclude that mitochondrial Ca2+ uptake is critical for age-related susceptibility to excitotoxicity and neuroprotection by NSAIDs. © 2014 International Society for Neurochemistry. Source

Santodomingo J.,Institute Biologia y Genetica Molecular IBGM | Santodomingo J.,University of Geneva | Fonteriz R.I.,Institute Biologia y Genetica Molecular IBGM | Lobaton C.D.,Institute Biologia y Genetica Molecular IBGM | And 3 more authors.
Cellular and Molecular Neurobiology | Year: 2010

We have investigated the dynamics of the free [Ca2+] inside the secretory granules of neurosecretory PC12 and INS1 cells using a low-Ca 2+-affinity aequorin chimera fused to synaptobrevin-2. The steady-state secretory granule [Ca2+] ([Ca2+] SG] was around 20-40 μM in both cell types, about half the values previously found in chromaffin cells. Inhibition of SERCA-type Ca2+ pumps with thapsigargin largely blocked Ca2+ uptake by the granules in Ca2+-depleted permeabilized cells, and the same effect was obtained when the perfusion medium lacked ATP. Consistently, the SERCA-type Ca2+ pump inhibitor benzohydroquinone induced a rapid release of Ca2+ from the granules both in intact and permeabilized cells, suggesting that the continuous activity of SERCA-type Ca2+ pumps is essential to maintain the steady-state [Ca2+]SG. Both inositol 1,4,5-trisphosphate (InsP3) and caffeine produced a rapid Ca2+ release from the granules, suggesting the presence of InsP 3 and ryanodine receptors in the granules. The response to high-K+ depolarization was different in both cell types, a decrease in [Ca2+]SG in PC12 cells and an increase in [Ca 2+]SG in INS1 cells. The difference may rely on the heterogeneous response of different vesicle populations in each cell type. Finally, increasing the glucose concentration triggered a decrease in [Ca 2+]SG in INS1 cells. In conclusion, our data show that the secretory granules of PC12 and INS1 cells take up Ca2+ through SERCA-type Ca2+ pumps and can release it through InsP3 and ryanodine receptors, supporting the hypothesis that secretory granule Ca 2+ may be released during cell stimulation and contribute to secretion. © 2010 Springer Science+Business Media, LLC. Source

Senovilla L.,Institute Biologia y Genetica Molecular IBGM | Nunez L.,Institute Biologia y Genetica Molecular IBGM | Nunez L.,University of Valladolid | de Campos J.M.,Hospital Universitario Del Rio Hortega | And 5 more authors.
Frontiers in Oncology | Year: 2015

Human pituitary tumors are generally benign adenomas causing considerable morbidity due to excess hormone secretion, hypopituitarism, and other tumor mass effects. Pituitary tumors are highly heterogeneous and difficult to type, often containing mixed cell phenotypes. We have used calcium imaging followed by multiple immunocytochemistry to type growth hormone secreting (GHomas) and non-functioning pituitary adenomas (NFPAs). Individual cells were typed for stored hormones and calcium responses to classic hypothalamic releasing hormones (HRHs). We found that GHomas contained growth hormone cells either lacking responses to HRHs or responding to all four HRHs. However, most GHoma cells were polyhormonal cells responsive to both thyrotropin-releasing hormone (TRH) and GH-releasing hormone. NFPAs were also highly heterogeneous. Some of them contained ACTH cells lacking responses to HRHs or polyhormonal gonadotropes responsive to LHRH and TRH. However, most NFPAs were made of cells storing no hormone and responded only to TRH. These results may provide new insights on the ontogeny of GHomas and NFPAs. © 2015 Senovilla, Núñez, de Campos, de Luis, Romero, García-Sancho and Villalobos. Source

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