GSK3 and β-catenin determines functional expression of sodium channels at the axon initial segment

Neuronal action potentials are generated through voltage-gated sodium channels, which are tethered by ankyrinG at the membrane of the axon initial segment (AIS). Despite the importance of the AIS in the control of neuronal excitability, the cellular and molecular mechanisms regulating sodium channel expression at the AIS remain elusive. Our results show that GSK3α/β and β-catenin phosphorylated by GSK3 (S33/37/T41) are localized at the AIS and are new components of this essential neuronal domain. Pharmacological inhibition of GSK3 or β-catenin knockdown with shRNAs decreased the levels of phosphorylated-β-catenin, ankyrinG, and voltage-gated sodium channels at the AIS, both “in vitro” and “in vivo”, therefore diminishing neuronal excitability as evaluated via sodium current amplitude and action potential number. Thus, our results suggest a mechanism for the modulation of neuronal excitability through the control of sodium channel density by GSK3 and β-catenin at the AIS.     

To be disordered or not to be disordered: is that still a question for proteins in the cell?

There is ample evidence that many proteins or regions of proteins lack a well-defined folded structure under native-like conditions. These are called intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). Whether this intrinsic disorder is also their main structural characteristic in living cells has been a matter of intense debate. The structural analysis of IDPs became an important challenge also because of their involvement in a plethora of human diseases, which made IDPs attractive targets for therapeutic development. Therefore, biophysical approaches are increasingly being employed to probe the structural and dynamical state of proteins, not only in isolation in a test tube, but also in a complex biological environment and even within intact cells. Here, we survey direct and indirect evidence that structural disorder is in fact the physiological state of many proteins in the proteome. The paradigmatic case of α-synuclein is used to illustrate the controversial nature of this topic.     

The generation of random ultrametric matrices representing dendrograms

Many methods and algorithms to generate random trees of many kinds have been proposed in the literature. No procedure exists however for the generation of dendrograms with randomized fusion levels. Randomized dendrograms can be obtained by randomizing the associated cophenetic matrix. Two algorithms are described. The first one generates completely random dendrograms, i.e., trees with a random topology, random fusion level values, and random assignment of the labels. The second algorithm uses a double-permutation procedure to randomize a given dendrogram; it proceeds by randomization of the fixed fusion levels, instead of using random fusion level values. A proof is presented that the double-permutation procedure is a Uniform Random Generation Algorithmsensu Furnas (1984), and a complete example is given. This work was supported by NSERC Grant No. A7738 to P. Legendre and by a NSERC scholarship to F.-J. Lapointe.     

Lipid packing sensed by ArfGAP1 couples COPI coat disassembly to membrane bilayer curvature

Protein coats deform flat lipid membranes into buds and capture membrane proteins to form transport vesicles. The assembly/disassembly cycle of the COPI coat on Golgi membranes is coupled to the GTP/GDP cycle of the small G protein Arf1. At the heart of this coupling is the specific interaction of membrane-bound Arf1-GTP with coatomer, a complex of seven proteins that forms the building unit of the COPI coat. Although COPI coat disassembly requires the catalysis of GTP hydrolysis in Arf1 by a specific GTPase-activating protein (ArfGAP1), the precise timing of this reaction during COPI vesicle formation is not known. Using time-resolved assays for COPI dynamics on liposomes of controlled size, we show that the rate of ArfGAP1-catalysed GTP hydrolysis in Arf1 and the rate of COPI disassembly increase over two orders of magnitude as the curvature of the lipid bilayer increases and approaches that of a typical transport vesicle. This leads to a model for COPI dynamics in which GTP hydrolysis in Arf1 is organized temporally and spatially according to the changes in lipid packing induced by the coat.     

Notes et documents sur la vie et l'œuvre de René Baire

Sans résumé Présenté par A. P. Youschkevitch     

Le principe de Weyl et l'invention d'une cosmologie non-statique

Sans résumé Présenté par J. D. North