Biophysical Society Thematic Meeting - October 13-15, 2015

Biophysics of Proteins at Surfaces: Assembly, Activation, Signaling

Poster Abstracts

30-POS Board 30 The Calcium Sensor NCS-1 as a Pharmacological Target for Synapse Regulation in Autism Alicia Mansilla 3 , Antonio Chaves-Sanjuán 1 , Nuria Campillo 2 , Carmen Gil 2 , Lourdes Infantes 1 , Ana Martinez 2 , Alberto Ferrus 3 , Maria Jose Sanchez-Barrena 1 . 1 Institute Rocasolano, CSIC, Madrid, Spain, 2 CIB, CSIC, Madrid, Spain, 3 Institute Cajal, CSIC, Madrid, Spain. Several forms of autism, including Fragile X syndrome (FXS), show an excess of synapses in brain cortex. Current strategies to counteract the excess of synapses focus in the design of drugs that antagonize postsynaptic glutamate receptors. This strategy, however, does not consider a general feature of neurons across nervous systems, which is the inverse correlation between the number of synapses and the probability of neurotransmitter release per synapse. Thus, it is most likely that the functional down-regulation of synapses will trigger an increase in synaptogenesis, which will lead to a spiral of ever increasing dosage in the pharmacological treatment to maintain the total synapse activity low. Recently we have described the mechanism by which these neuronal features are co-regulated by the myristoylated Ca 2+ -sensor NCS-1 and its binding partner Ric8a, a GEF that activates G protein complexes. Structural studies demonstrated the key residues on NCS-1 necessary for NCS-1/Ric8a complex formation. Altogether our data suggest that if we were able to disrupt the NCS1/Ric8 complex with small compounds, it would be possible to use them as therapeutic drugs to decrease the number of synapsis in mental disorders where synapse number is abnormal. Using virtual screening methods we have found an amino- phenothiazine-class molecule that impedes complex formation and re-establishes synapse function in FXS model of Drosophila. Crystallographic data on the NCS-1/small compound complex shows the reason of the inhibition. This structure will permit us to improve the pharmacological properties of the molecule for a future use as therapeutic drug. References: J Romero-Pozuelo, JS Dason, A Mansilla, S Baños-Mateos, JL Sardina, A Chaves-Sanjuán, J Jurado-Gómez, E Santana, HL Atwood, A Hernández-Hernández, MJ Sánchez-Barrena, A Ferrús. J. Cell Sci., 2014. S Baños-Mateos, A Chaves-Sanjuán, A Mansilla, A Ferrús, MJ Sánchez-Barrena. Acta Cryst F, 2014.

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