Interference 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...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2017-02, Vol.114 (6), p.E999-E1008
Main Authors: Mansilla, Alicia, Chaves-Sanjuan, Antonio, Campillo, Nuria E., Semelidou, Ourania, Martínez-González, Loreto, Infantes, Lourdes, González-Rubio, Juana María, Gil, Carmen, Conde, Santiago, Skoulakis, Efthimios M. C., Ferrús, Alberto, Martínez, Ana, Sánchez-Barrena, María José
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antipsychotic Agents - chemistry
Antipsychotic Agents - pharmacology
Biological Sciences
Calcium
Crystallography, X-Ray
Disease Models, Animal
Drosophila
Drosophila melanogaster - genetics
Drosophila melanogaster - metabolism
Drosophila Proteins - chemistry
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Fragile X Syndrome - genetics
Fragile X Syndrome - metabolism
Genetic disorders
Guanine Nucleotide Exchange Factors - chemistry
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - metabolism
Humans
Insects
Models, Molecular
Molecular Structure
Neuronal Calcium-Sensor Proteins - chemistry
Neuronal Calcium-Sensor Proteins - genetics
Neuronal Calcium-Sensor Proteins - metabolism
Neurons
Neuropeptides - chemistry
Neuropeptides - genetics
Neuropeptides - metabolism
Phenothiazines - chemistry
Phenothiazines - pharmacology
PNAS Plus
Protein Binding - drug effects
Protein Domains
Proteins
Sequence Homology, Amino Acid
Synapses - genetics
Synapses - metabolism
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Summary: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-1. The crystal structure of NCS-1 bound to FD44 and the structure–function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1611089114