Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

Abstract

Background: Current pharmacological treatments for schizophrenia target G protein-coupled receptors (GPCRs), including dopamine receptors. Ligand-bound GPCRs are regulated by a family of G protein-coupled receptor kinases (GRKs), members of which uncouple the receptor from heterotrimeric G proteins, desensitize the receptor, and induce receptor internalization via the arrestin family of scaffolding and signaling molecules. GRKs initiate the activation of downstream signaling pathways, can regulate receptors and signaling molecules independent of GPCR phosphorylation, and modulate epigenetic regulators like histone deacetylases (HDACs). We hypothesize that the expression of GRK proteins is altered in schizophrenia, consistent with previous findings of alterations upstream and downstream from this family of molecules that facilitate intracellular signaling processes.

Methods: In this study, we measured protein expression via Western blot analysis for GRKs 2, 3, 5, and 6 in the anterior cingulate cortex of patients with schizophrenia (n=36) and a comparison group (n=33). To control for antipsychotic treatment, we measured these same targets in haloperidol-treated vs. untreated rats (n=10 for both).

Results: We found increased levels of GRK5 in schizophrenia. No changes were detected in GRK protein expression in rats treated with haloperidol decanoate for 9 months.

Conclusion: These data suggest that increased GRK5 expression may contribute to the pathophysiology of schizophrenia via abnormal regulation of the cytoskeleton, endocytosis, signaling, GPCRs, and histone modification.

Keywords: G protein-coupled receptor (GPCR); G protein-coupled receptor kinase (GRK); Histone deacetylase (HDAC); Kinase; Postmortem; Schizophrenia.

Figure 1

GRK Protein Expression in Anterior Cingulate Cortex in Schizophrenia. Protein expression for GRK5 was increased in subjects with schizophrenia. GRK2, GRK3, and GRK6 protein levels did not differ between groups. Protein expression values were normalized to VCP as an in-lane loading control. *p < 0.05, C = comparison group, S = schizophrenia group.

Figure 2

GRK Protein Expression in Anterior Cortex of Haloperidol Decanoate Treated Rats. Protein levels did not differ between rats treated with haloperidol decanoate for 9 months and vehicle. Protein expression values were normalized to VCP as an in-lane loading control. C = vehicle, H = haloperidol decanoate treated.