The σ1receptor (S1R) is a ligand-regulated
non-opioid
intracellular receptor involved in several pathological conditions.
The development of S1R-based drugs as therapeutic agents is a challenge
due to the lack of simple functional assays to identify and classify
S1R ligands. We have developed a novel nanoluciferase binary technology
(NanoBiT) assay based on the ability of S1R to heteromerize with the
binding immunoglobulin protein (BiP) in living cells. The S1R-BiP
heterodimerization biosensor allows for rapid and accurate identification
of S1R ligands by monitoring the dynamics of association–dissociation
of S1R and BiP. Acute treatment of cells with the S1R agonist PRE-084
produced rapid and transient dissociation of the S1R-BiP heterodimer,
which was blocked by haloperidol. The effect of PRE-084 was enhanced
by calcium depletion, leading to a higher reduction in heterodimerization
even in the presence of haloperidol. Prolonged incubation of cells
with S1R antagonists (haloperidol, NE-100, BD-1047, and PD-144418)
increased the formation of S1R-BiP heteromers, while agonists (PRE-084,
4-IBP, and pentazocine) did not alter heterodimerization under the
same experimental conditions. The newly developed S1R-BiP biosensor
is a simple and effective tool for exploring S1R pharmacology in an
easy cellular setting. This biosensor is suitable for high-throughput
applications and a valuable resource in the researcher’s toolkit.