The purpose of this project is to understand the role of animal-derived lectins in nervous system activity. Investigation into the neuronal activities of galectins, a family of mammalian soluble galactoside-binding proteins, thus far has focused primarily on how they impact neurogenesis or act as metastatic factors for brain cancer cells. However, galectins also are known to be secreted by glia and neurons in the mature nervous system, and therefore are likely to have a physiological role in brain function. We hypothesize that galectins impact neuronal function through short-term morphological changes in dendritic spines, alterations in synaptic plasticity, and reductions in neuronal viability. These activities re mediated by engagement of intracellular signaling cascades that include ERK/MAPK. Integral proteins expressed on neuronal plasma membranes typically contain the glycan N acetyllactosamine, a common disaccharide constituent of complex oligosaccharides, and therefore could serve as targets for galectin binding and cross-linking of signaling molecules, leading to their activation and initiation of intracellular enzymatic cascades. In addition to thei actions on neurons, galectins are useful tools for understanding the relevance of N-glycans to ionotropic glutamate receptor (iGluR) function due to their allosteric modulatory actions. Accordingly, the proposed project will elucidate how galectins impact neuronal function and viability and use these proteins as glycan-specific tools in structure-function studies with recombinant iGluRs.
In Specific Aim 1, we will examine galectin activity on neurotransmission and synaptic plasticity in the mouse hippocampus. Experiments in Specific Aim 2 will test the hypothesis that galectins alter neuronal structural plasticity through intracellular kinase cascades. Finally, in Specific Aim 3, we will determine the spectrum of galectin actions on iGluRs and their molecular basis. We will probe the physical characteristics of galectins that optimize their functional action on iGluRs. These studies will yield insight into the as-yet unexplored relevance of galectins to neuronal function, which also will be relevant to understanding their importance to glioma-induced alterations in neuronal excitability.
We will determine how galectins, a family of proteins secreted by many types of cells, impact neuronal signaling and viability. We also will explore specific interactions with glutamate receptors as a way of testing the importance of integral sugar molecules to receptor function. This research is relevant to understanding how galectins impact normal brain function as well as how they might induce aberrant behavior of neurons in the presence of brain tumors, which secrete high levels of galectin protein.
|Sakai, Ryuichi; Swanson, Geoffrey T (2014) Recent progress in neuroactive marine natural products. Nat Prod Rep 31:273-309|
|Copits, Bryan A; Vernon, Claire G; Sakai, Ryuichi et al. (2014) Modulation of ionotropic glutamate receptor function by vertebrate galectins. J Physiol 592:2079-96|