Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in eLife 6 (2017): e25651, doi:10.7554/eLife.25651.To better understand smoking cessation, we examined the actions of varenicline (Chantix) during long-term nicotine exposure. Varenicline reduced nicotine upregulation of α4β2-type nicotinic receptors (α4β2Rs) in live cells and neurons, but not for membrane preparations. Effects on upregulation depended on intracellular pH homeostasis and were not observed if acidic pH in intracellular compartments was neutralized. Varenicline was trapped as a weak base in acidic compartments and slowly released, blocking 125I-epibatidine binding and desensitizing α4β2Rs. Epibatidine itself was trapped; 125I-epibatidine slow release from acidic vesicles was directly measured and required the presence of α4β2Rs. Nicotine exposure increased epibatidine trapping by increasing the numbers of acidic vesicles containing α4β2Rs. We conclude that varenicline as a smoking cessation agent differs from nicotine through trapping in α4β2R-containing acidic vesicles that is selective and nicotine-regulated. Our results provide a new paradigm for how smoking cessation occurs and suggest how more effective smoking cessation reagents can be designed.This work was supported by National Institutes of Health RO1DA 035430 and a Pilot Project from the University of Chicago Can- cer Center

Maritime-oriented foragers during the Late Pleistocene on the eastern costa del sol (Southeast Iberia): Cueva Victoria (Málaga, Spain)

The Mediterranean coast of Spain is marked by several clusters of Palaeolithic sites: to the south of the Pyrenees, in the area around the Ebro River, in the central part, and on the south coast, one of the southernmost regions in Europe. The number of sites is small compared with northern Iberia, but like that region, the Palaeolithic occupations are accompanied by several rock art ensembles. The archaeological material (both biotic and abiotic resources) and radiocarbon dates presented here were obtained during archaeological fieldwork of professor J. Fortea in the Late Pleistocene deposits in Cueva Victoria, located near the modern coastline and about 150 km north of the Strait of Gibraltar. In the three occupation phases, marine resources were acquired by shell-fishing (focusing almost exclusively on the clam Ruditapes decussatus), fishing, and the use of beached marine mammals. This contrasts with the limited data about the exploitation of terrestrial resources by hunting and gathering animals and plants. The study is completed by the study of artefacts (lithic and bone industry and objects of adornment) that help to understand the subsistence strategies of the cave occupants and enable a comparison with other groups inhabiting the Mediterranean coasts of the Iberian Peninsula during Greenland Interstadial 1, between ca. 15.1 and 13.6 cal BP.This work was supported by the University of Salamanca GIR PREHUSAL, the Ministry of Science and Innovation-Spanish Government (PaleontheMove-PID2020-114462GB-I00), the Universidad Nacional de Educación a Distancia (Madrid) and Dirección General de Universitat, Investigacio i Ciencia of the Valencian Regional Government (Project Aico/2020/97).Peer reviewe

Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation

To better understand smoking cessation, we examined the actions of varenicline (Chantix) during long-term nicotine exposure. Varenicline reduced nicotine upregulation of α4β2-type nicotinic receptors (α4β2Rs) in live cells and neurons, but not for membrane preparations. Effects on upregulation depended on intracellular pH homeostasis and were not observed if acidic pH in intracellular compartments was neutralized. Varenicline was trapped as a weak base in acidic compartments and slowly released, blocking 125I-epibatidine binding and desensitizing α4β2Rs. Epibatidine itself was trapped; 125I-epibatidine slow release from acidic vesicles was directly measured and required the presence of α4β2Rs. Nicotine exposure increased epibatidine trapping by increasing the numbers of acidic vesicles containing α4β2Rs. We conclude that varenicline as a smoking cessation agent differs from nicotine through trapping in α4β2R-containing acidic vesicles that is selective and nicotine-regulated. Our results provide a new paradigm for how smoking cessation occurs and suggest how more effective smoking cessation reagents can be designed

Las plantas medicinales en el inventario español sobre los conocimientos Tradicionales relativos al patrimonio natural y a la biodiversidad

En las últimas décadas las organizaciones internacionales han puesto de manifiesto la importancia de los conocimientos ecológicos tradicionales para la conservación y el uso sostenible de la diversidad biológica, como se refleja en el Convenio sobre la Diversidad Biológica (CBD 1992). En España, el marco jurídico que recoge las normas y recomendaciones de esta estrategia es la Ley de Patrimonio Natural y Biodiveresidad 42/2007 que establece la creación del Inventario Español de Conocimientos Tradicionales (IECT) relevantes para la conservación y el uso sostenible de la biodiversidad y geodiversidad. Desde hace más de un año un equipo de más de 60 investigadores, incluyendo botánicos, zoólogos, antropólogos, ecólogos y geólogos de más de 20 centros de investigación y universidades del estado español, están trabajando en el IEDT, con el objetivo de recopilar y difundir la información publicada sobre los conocimientos tradicionales relativos a la flora, fauna, geodiversidad y el manejo de los ecosistemas

Ús i abús de la natura, impactes i propostes de gestió. El cas de Catalunya com a paradigma

78 pages, 10 figures, 20 tablesFem aquí un balanç dels darrers quaranta anys d'ús, en molts casos abús, dels recursos naturals a Catalunya, un país representatiu dels països europeus, en especial dels mediterranis. [...]Peer reviewe