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Tuning wavelength and G protein specificty of Melanopsin for optogenetic control of G protein signaling pathways.

Subject Area Molecular Biology and Physiology of Neurons and Glial Cells
Biophysics
Structural Biology
Term from 2016 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 315212873
 
Our goal is to create optogenetic tools for independent control of intracellular G protein signals activated by the Gi/o and Gs, but in particular the Gq/11 pathway. These tools will be established using vertebrate melanopsin and neuropsin as light-activated G protein coupled receptor (GPCR), which activates Gq11 and Gi/o pathways in neurons, heart and heterologous expression systems. Computer models (Gerwert lab) will predict amino acid position critical for wavelength specificity, bistabililty, and G protein selectivity. The functional analysis (Brügmann & Herlitze lab) of amino acid changes at predicted position using electrophysiological recordings and imaging techniques will provide experimental feedback for new working models of melanopsin and neuropsin and their G protein selectivity. Vertebrate melanopsin and neuropsin as bistable pigments are preferable over commonly used opsins to control G protein pathways in particular for highly-repetitive in vivo applications, because it can be switched on and off by two different wavelength of visible light. In addition, sustained G protein signals can be activated by short light pulses, reducing phototoxicity. These tools will be applicable for controlling every GPCR coupling to the common G protein pathways, such as dopamine, adreno, metabotropic glutamate, histamine or orexin receptor pathways without change in signal kinetics. Because of our long-standing interest in serotonin, we will tailor these tools to specifically control G protein signals in 5HT receptor signaling domains. The ultimate goal is to control two signaling pathways simultaneously, but independently by two different wavelength of light to understand how G protein signals synergistically and/or independently act to modulate cell function and behavior. In order to perform these experiments we have assembled a team of three experts on the development of optogenetic tools (Brügmann & Herlitze) and computational modeling of protein structures (Gerwert).
DFG Programme Priority Programmes
 
 

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