Analysis of the protein nano-environment of voltage-activated N-type Ca2+ channels Cav2.2 in the brain

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Voltage-gated N-type calcium channels (Cav2.2) trigger a variety of process in the CNS including function, formation and plasticity of synapses, activity-dependent gene expression and regulation of excitability and propagation of electrical signaling. Using comprehensive and quantitative proteomics on the molecular nano-environment of these channels we have identified the framework for their marked diversity in function: Cav2.2 channels are integrated into extended protein networks that may be assembled from a pool of ~160 proteins (at distinct abundance and stability of association) and reflect the cellular processes that can be fueled by Cav2.2 channels. The next funding period aims at the understanding (i) of the molecular structure and organization of the Cav2.2 channel networks, (ii) their local specificity and dynamics of assembly (do networks depend on the types of synapse/brain regions, on cellular boundaries such as neuronal activity and/or the presence of 'hub proteins'?), as well as on (iii) protein-protein interactions decisive for the operation of Cav2.2 nano-environments. For these goals we will apply a multidisciplinary approach comprising interactive application of an array of techniques including high-resolution quantitative mass spectrometry, biochemistry, standard molecular biology, immunocytochemistry and immunoelectron microscopy and electrophysiology.