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000860921 1001_ $$00000-0003-4632-8100$$aCapaldi, Stefano$$b0
000860921 245__ $$aAllosteric sodium binding cavity in GPR3: a novel player in modulation of Aβ production
000860921 260__ $$a[London]$$bMacmillan Publishers Limited, part of Springer Nature$$c2018
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000860921 520__ $$aThe orphan G-protein coupled receptor 3 (GPR3) belongs to class A G-protein coupled receptors (GPCRs) and is highly expressed in central nervous system neurons. Among other functions, it is likely associated with neuron differentiation and maturation. Recently, GPR3 has also been linked to the production of Aβ peptides in neurons. Unfortunately, the lack of experimental structural information for this receptor hampers a deep characterization of its function. Here, using an in-silico and in-vitro combined approach, we describe, for the first time, structural characteristics of GPR3 receptor underlying its function: the agonist binding site and the allosteric sodium binding cavity. We identified and validated by alanine-scanning mutagenesis the role of three functionally relevant residues: Cys2676.55, Phe1203.36 and Asp2.50. The latter, when mutated into alanine, completely abolished the constitutive and agonist-stimulated adenylate cyclase activity of GPR3 receptor by disrupting its sodium binding cavity. Interestingly, this is correlated with a decrease in Aβ production in a model cell line. Taken together, these results suggest an important role of the allosteric sodium binding site for GPR3 activity and open a possible avenue for the modulation of Aβ production in the Alzheimer's Disease.
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000860921 7001_ $$0P:(DE-HGF)0$$aSuku, Eda$$b1
000860921 7001_ $$0P:(DE-HGF)0$$aAntolini, Martina$$b2
000860921 7001_ $$0P:(DE-HGF)0$$aDi Giacobbe, Mattia$$b3
000860921 7001_ $$0P:(DE-Juel1)165199$$aGiorgetti, Alejandro$$b4$$eCorresponding author
000860921 7001_ $$0P:(DE-HGF)0$$aBuffelli, Mario$$b5
000860921 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/s41598-018-29475-7$$gVol. 8, no. 1, p. 11102$$n1$$p11102$$tScientific reports$$v8$$x2045-2322$$y2018
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