Allosteric sodium binding cavity in GPR3: a novel player in modulation of Aβ production

Sci Rep. 2018 Jul 23;8(1):11102. doi: 10.1038/s41598-018-29475-7.


The 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Amyloid beta-Peptides / metabolism*
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Mutant Proteins / metabolism
  • Onium Compounds / metabolism
  • Point Mutation / genetics
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Sodium / metabolism*
  • Structural Homology, Protein
  • beta-Arrestins / metabolism


  • Amyloid beta-Peptides
  • GPR3 protein, human
  • Mutant Proteins
  • Onium Compounds
  • Receptors, G-Protein-Coupled
  • beta-Arrestins
  • diphenyleneiodonium
  • Sodium