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Molecular events for neuronal function and dysfunction

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The process by which signaling molecules called neurotransmitters are released by a neuron (the presynaptic neuron), and bind the receptors of another neuron (the postsynaptic neuron) is defined as ‘synaptic transmission’ and it is the key for neuronal communication.

The synaptic transmission 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.

Our Institute is currently devoted to develop and apply High Performance Computing (HPC)-based simulations to design potent ligands for therapeutic and diagnostic purposes, as well as to study chemical senses. Multiscale molecular simulations are complemented by free energy calculations and bioinformatics to study GPCRs and their cascades. To bridge the gap between the molecular description and a more systemic-oriented investigations, the Institute is also developing mesoscale models of post-synaptic signaling events.

Drug Design PipelineDrug Design Pipeline: early steps


The ligand development program is in coordination with several experimental groups within INM, FZJ and beyond. In silico pharmacology, molecular simulations, free energy calculations and bioinformatics are here exploited to rational design of molecules for technology advances in brain imaging, neuronal disease genetics and neuropharmacology.

Neuronal function (and dysfunction) indeed depend on exquisite molecular recognition processes during which specific biomolecules bind to each other allowing neuronal signaling. The detailed understanding of these processes, as well as the response to ligand-based treatment, require the characterization of neuronal biomolecules’ structure, function, dynamics, and energetics, in an environment as close as possible to that of neurons (see e.g. here).

Within the Human Brain Project our group, in collaboration with several European labs (the BISI lab of the Institut de Biologie et Chimie des Protéines at Lyon (France), the Molecular and Chemical Modelling group at the Heidelberg Institute for Theoretical Studies (Germany), the Molecular Modelling and Bioinformatics group of the IRB Barcelona (Spain), the Laboratory of Computational Chemistry and Biochemistry at EPFL Lausanne (Switzerland)) is investigating GPCRs-induced neuronal cascades governing key memory and learning processes.

Neuron model

To address these challenging issues, the Institute develops and uses a variety of integrated computational methods. Multiscale molecular simulations are complemented by free energy calculations and bioinformatics to study GPCRs and their cascades. To bridge the gap between the molecular description and a more systemic-oriented modeling, we are creating at the same time a collaborative transverse group between our Institute and the Institute of Complex System ICS3 at FZJ, working on the mesoscale modeling of post-synaptic signaling events. Using some of the 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.


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