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In the synaptic transmission, signaling molecules (neurotransmitters) are released by a neuron (the presynaptic one) to bind the receptors of another neuron (the postsynapic one). This process is one of the key events underlying neuronal communication. It consists of a series of chemical reactions that are initiated by a stimulus (first messenger), acting on a receptor that is transduced to the cell interior through second messengers (which amplify the initial signal) and ultimately to effector molecules, resulting in a cell response to the initial stimulus. This downstream chemical activity leads to diverse biological responses, from gene expression to synaptogenesis. At each step of the signal cascade, a variety of proteins are involved, as well as various controlling factors. A large number of signaling cascades are governed by G-Protein Coupled Receptors (GPCRs). These are key targets for therapeutic intervention as well as for neuroimaging in the diagnosis of the disease. Neuronal GPCRs are also key proteins for human senses, including olfaction, bitter taste and vision.

GPCR signal trasduction cascadeA. (Left) GPCRs structure: extracellular amino terminus (Nt), seven transmembrane ?-helices (TM1-7), three intracellular (IL1-3) and three extracellular loops (EL1-3), intracellular carboxyl terminus (Ct); (right) GPCR’s barrel-like tertiary structure. B. Important brain signaling cascades, involving GPCR and ligand-gated ion channel (LGICs), are started by the binding of a neurotransmitter (NT, 1st messenger), whose effect is progressively amplified (2nd, 3rd, 4th messenger) by intracellular proteins.

Multiscale molecular simulations are complemented by free energy calculations and bioinformatics to study GPCRs and their cascades. Our Institute also develops and applies High Performance Computing (HPC)-based simulations to design potent ligands for therapeutic and diagnostic purposes, as well as to study chemical senses GPCRs. To bridge the gap between the molecular description and a more systemic-oriented investigations, the Institute is developing mesoscale models of post-synaptic signaling events. This is supported by collaborative transverse group between our Institute and the Institute of Complex System ICS-3 at FZJ. Using some of the GPCRs cascades involved in human memory processes as test cases, we model the essential physicochemical mechanisms controlling the correct timing of the molecular events shaping the neuronal signaling.