The main goal of CellCellEM is to delineate cellular communication through understanding signaling at the structural and at the molecular levels. The project was designed to primarily characterize the structure and function of individual signaling proteins residing at the cellular membrane, but also to understand the way they communicate with their partners within the cell, outside the cell, and inside the cellular membrane. Specifically, the project focused on a family of adhesion GPCRs, the latrophilins, that are highly abundant in the CNS and are known to maintain multifaced interactions with proteins within the cell, the cellular membrane and in neighboring cells. However, while the initial scope of the project was to focus on this family of proteins, the project expanded way beyond the current scope, both through working on additional CNS proteins (e.g. other GPCRs) and also for the exploration of the evolutionary evolvement of signaling. These two avenues culminated in an ongoing work in our group that lead to the discovery of a novel family of proteins, the bestrhodopsins, that are light activated ion channels composed of rhodopsins fused to bestrophin ion channels, and at the determination of additional GPCR structures of other components of the CNS. A paper describing the bestrhodopsin discovery was recently published by our group (Rozenberg et al. Nature Struct. Mol. Biol. 2022), while the later studies on GPCRs are currently in final preparations of manuscripts to be sent within the next few weeks. The study on bestrhodopsins is currently ongoing in the lab and as rhodopsins are considered to be ancestors of GPCRs, these studies may potentially provide hints regarding the evolution of signaling mechanisms and aid in understanding the inner workings of the more complex signaling pathways in our brain. Altogether these studies are an evolvement of the suggested ERC project and are conducted in parallel to our work on the explicit aims 2 and 3 mentioned in the proposal, that are aimed at the structural and functional studies of latrophilins with their extracellular partners.