biostudies-literatureUnknown114(6)Mansilla AThe protein complex formed by the Ca²⁺ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-Proceedings of the National Academy of Sciences of the United States of AmericaE999-E1008https://www.ebi.ac.uk/biostudies/studies/S-EPMC5307446biostudies-literatureInterference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome.PMC5307446Sanchez-Barrena MJCampillo NEGonzalez-Rubio JMSemelidou OFerrus AInfantes LGil CMartinez-Gonzalez LMansilla AMartinez ASkoulakis EMChaves-Sanjuan AConde SfalseInterference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome.The protein complex formed by the Ca²⁺ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-2017-01-01T00:00:00Z2017 Feb2025-04-05T09:35:15.315Z2019-03-27T02:36:25ZS-EPMC53074462811950010.1073/pnas.1611089114