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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.