Identification of regulatory proteins of acid-sensing ion channels.

Acid-sensing ion channels (ASICs) are voltage-independent proton-gated ion channels belonging to the amiloride-sensitive degenerin/epithelial Na+ channel (DEG/ENaC) family of receptor channels. Six subunits (ASICla, lb, 2a, 2b, 3 and 4) encoded for by four genes, have been identified so far. All ASIC subunits are expressed in dorsal root ganglia (DRG) and have been implicated in physiological sensory processes such as nociception associated with tissue acidosis, cutaneous and visceral mechanosensation, sour taste and cochlear function. However, some ASIC subunits also show a wide distribution throughout the brain, where they are thought to modulate synaptic communication. Supporting this hypothesis several studies demonstrated in mice a role for ASICs in learning, memory and fear behaviour. Recently ASIC la channels were also shown to make a major contribution to hippocampal neuronal damage in stroke through Ca2+ overload. ASIC4 is broadly expressed in the nervous system but is not gated by protons and has no known function. This thesis describes a genetic analysis carried out to identify interacting partners of ASICs in sensory neurons, in order to shed light on the possible role of ASIC4, and to better understand the functional roles of ASIC 1-3 and their regulatory mechanisms. A rat dorsal root ganglion cDNA library was screened in a yeast two-hybrid assay and a number of proteins interacting with the N-terminal domain of rat ASIC 1-4 were trapped. Many of these proteins were involved in trafficking of ion channels, G protein pathways, endocytosis, protein ubiquitination, or cell adhesion, suggesting potentially novel roles and regulatory mechanisms for ASIC channels. The annexin II light chain pll was found to specifically interact with ASIC la, and to promote its functional expression at the plasma membrane, as shown by immunocytochemistry, cell surface protein biotinylation and electrophysiology. ASIC4 was shown to decrease the protein level of other ASIC subunits, and to downregulate ASIC la-mediated currents. Preliminary data suggest that this effect may be due to an involvement of ASIC4 in ubiquitination pathways. Overall, this work has led to the identification of interacting proteins that regulate ASICs and suggested novel functions for ASIC4

L1CAM binds ErbB receptors through Ig-like domains coupling cell adhesion and neuregulin signalling.

During nervous system development different cell-to-cell communication mechanisms operate in parallel guiding migrating neurons and growing axons to generate complex arrays of neural circuits. How such a system works in coordination is not well understood. Cross-regulatory interactions between different signalling pathways and redundancy between them can increase precision and fidelity of guidance systems. Immunoglobulin superfamily proteins of the NCAM and L1 families couple specific substrate recognition and cell adhesion with the activation of receptor tyrosine kinases. Thus it has been shown that L1CAM-mediated cell adhesion promotes the activation of the EGFR (erbB1) from Drosophila to humans. Here we explore the specificity of the molecular interaction between L1CAM and the erbB receptor family. We show that L1CAM binds physically erbB receptors in both heterologous systems and the mammalian developing brain. Different Ig-like domains located in the extracellular part of L1CAM can support this interaction. Interestingly, binding of L1CAM to erbB enhances its response to neuregulins. During development this may synergize with the activation of erbB receptors through L1CAM homophilic interactions, conferring diffusible neuregulins specificity for cells or axons that interact with the substrate through L1CAM

The SURFEXv7.2 land and ocean surface platform for coupled or offline simulation of Earth surface variables and fluxes

CC Attribution 3.0 License.Final revised paper also available at http://www.geosci-model-dev.net/6/929/2013/gmd-6-929-2013.pdfInternational audienceSURFEX is a new externalized land and ocean surface platform that describes the surface fluxes and the evolution of four types of surface: nature, town, inland water and ocean. It can be run either coupled or in offline mode. It is mostly based on pre-existing, well validated scientific models. It can be used in offline mode (from point scale to global runs) or fully coupled with an atmospheric model. SURFEX is able to simulate fluxes of carbon dioxide, chemical species, continental aerosols, sea salt and snow particles. It also includes a data assimilation module. The main principles of the organization of the surface are described first. Then, a survey is made of the scientific module (including the coupling strategy). Finally the main applications of the code are summarized. The current applications are extremely diverse, ranging from surface monitoring and hydrology to numerical weather prediction and global climate simulations. The validation work undertaken shows that replacing the pre-existing surface models by SURFEX in these applications is usually associated with improved skill, as the numerous scientific developments contained in this community code are used to good advantage