Phosphorylation-Elicited Quaternary Changes of GA Binding Protein in Transcriptional Activation

Enrichment of nicotinic acetylcholine receptors (nAChR) on the tip of the subjunctional folds of the postsynaptic membrane is a central event in the development of the vertebrate neuromuscular junction. This is attained, in part, through a selective transcription in the subsynaptic nuclei, and it has recently been shown that the GA binding protein (GABP) plays an important role in this compartmentalized expression. The neural factor heregulin (HRG) activates nAChR transcription in cultured cells by stimulating a signaling cascade of protein kinases. Hence, it is speculated that GABP becomes activated by phosphorylation, but the mechanism has remained elusive. To fully understand the consequences of GABP phosphorylation, we examined the effect of heregulin-elicited GABP phosphorylation on cellular localization, DNA binding, transcription, and mobility. We demonstrate that HRG-elicited phosphorylation dramatically changes the transcriptional activity and mobility of GABP. While phosphorylation of GABPβ seems to be dispensable for these changes, phosphorylation of GABPα is crucial. Using fluorescence resonance energy transfer, we furthermore showed that phosphorylation of threonine 280 in GABPα triggers reorganizations of the quaternary structure of GABP. Taken together, these results support a model in which phosphorylation-elicited structural changes of GABP enable engagement in certain interactions leading to transcriptional activation

Reduced antinociception in mice lacking neuronal nicotinic receptor subunits.

Nicotine exerts antinociceptive effects by interacting with one or more of the subtypes of nicotinic acetylcholine receptors (nAChRs) that are present throughout the neuronal pathways that respond to pain. To identify the particular subunits involved in this process, we generated mice lacking the alpha4 subunit of the neuronal nAChR by homologous recombination techniques and studied these together with previously generated mutant mice lacking the beta2 nAChR subunit. Here we show that the homozygous alpha4-/- mice no longer express high-affinity [3H]nicotine and [3H]epibatidine binding sites throughout the brain. In addition, both types of mutant mice display a reduced antinociceptive effect of nicotine on the hot-plate test and diminished sensitivity to nicotine in the tail-flick test. Patch-clamp recordings further reveal that raphe magnus and thalamic neurons no longer respond to nicotine. The alpha4 nAChR subunit, possibly associated with the beta2 nAChR subunit, is therefore crucial for nicotine-elicited antinociception.Journal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.info:eu-repo/semantics/publishe

The Asian side of the world

Asia and the Pacific, an immense region, both new and old, in which two thirds of the world lives. A region of superlatives, exceptions, China, continually facing disasters and risks from its past, India, a continent of its own, Japan, archipelago of the future. It is a region that is attracting global growth and becoming the centre of the world. Who could have predicted that the GDP of Asia and the Pacific would be equal to that of the European Union? And what will tomorrow bring? This compilation gives an overview of Asia's world, bringing together roughly a hundred texts written by researchers and specialists and that have been published on Asia and the Pacific Network's website (CNRS/FMSH) between 2002 and 2011. These works covering the humanities and social science recount the past, tell us of the future and illustrate the complexity of Asia and the Pacific through its flaws, strengths and challenges. They reveal the profound roots and depth of the dynamism of these new powers that could soon take over the future of humanity. Numerous researchers and academics specialising in contemporary Asia and the Pacific are bringing into light many aspects of this great and inevitable shift in the world