GPR56/ADGRG1 is associated with response to antidepressant treatment

Abstract

It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotoninnorepinephrine reuptake inhibitor (N = 424) we show that responders, but not nonresponders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/ GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.

Orphan G Protein Coupled Receptors in Affective Disorders

“…Recent findings have shown the association of another adhesion GPCR with depression—ADGRG1 (GPR56) [ 66 ]. As described for ADGRB2, the mechanism of ADGRG1 activation involves the self-cleavage of its long ectodomain to expose a stimulating tethered ligand [ 98 , 99 ].…”

“…ADGRG1 mRNA in blood cells was up-regulated in response to a variety of antidepressant treatments, but, importantly, only in patients responding to the therapy and not in respondent patients treated with placebo [ 66 ]. Remarkably, transcriptomic studies on post-mortem brain tissues from MDD patients and control subjects revealed a significant down-regulation of ADGRG1 in the dorsolateral PFC [ 59 ].…”

An Exploratory Pilot Study with Plasma Protein Signatures Associated with Response of Patients with Depression to Antidepressant Treatment for 10 Weeks

“…We downloaded the gene expression profile data (series accession number: GSE146446 [26] and GSE45468 [27]) in the Gene Expression Omnibus database for using Biobase and GEOquery package in R. Both data used the GPL570 platform (Affymetrix Human Genome U133 Plus 2.0 Array; Agilent Technologies, Palo Alto, CA, USA). We found the Affymetrix probe IDs by searching for the gene name.…”

“…Among them, CALU represented significance for the treatment/time/response interaction term (p-value < 0.05), and CTSD and SH3BGRL3 represented significance for the treatment/response interaction term (p-value < 0.05; Figure 3B). Because we could not find a benchmark study on blood protein-based drug responsiveness to antidepressants, we examined the expression patterns of LMM-significant 37 proteins described in the results of large-scale studies at the blood circulating cell-free mRNA level from two publicly available GEO datasets-(GSE146446 [26] and GSE45468 [27]). Unlike the proteomic study above, the two GEO studies contained results on the effects of patients receiving a placebo.…”

Specific and direct modulation of the interaction between adhesion GPCR GPR56/ADGRG1 and tissue transglutaminase 2 using synthetic ligands

“…GPR56/ADGRG1 belongs to the aGPCR family and plays a critical role in diverse pathophysiological processes such as brain development 12,[23][24][25][26][27] , major depressive disorder 28 , peripheral immunity 29,30 , CNS immunity 31 , skeletal muscle development [32][33][34] , pancreatic beta-cell function 35,36 , and cancer progression [37][38][39][40][41][42][43] . We have shown that the GPR56 ECR is composed of an N-terminal pentraxin and laminin/neurexin/sex hormone-binding globulin (PLL) domain and a juxtamembrane GPCR autoproteolysis-inducing (GAIN) domain and that the ECR plays a receptor-autonomous regulatory role in G protein signaling 12 .…”