Serine racemase binds to PICK1: potential relevance to schizophrenia

Abstract

Accumulating evidence from both genetic and clinico-pharmacological studies suggests that D-serine, an endogenous coagonist to the NMDA subtype glutamate receptor, may be implicated in schizophrenia (SZ). Although an association of genes for D-serine degradation, such as D-amino acid oxidase and G72, has been reported, a role for D-serine in SZ has been unclear. In this study, we identify and characterize protein interacting with C-kinase (PICK1) as a protein interactor of the D-serine synthesizing enzyme, serine racemase (SR). The binding of endogenous PICK1 and SR requires the PDZ domain of PICK1. The gene coding for PICK1 is located at chromosome 22q13, a region frequently linked to SZ. In a case-control association study using well-characterized Japanese subjects, we observe an association of the PICK1 gene with SZ, which is more prominent in disorganized SZ. Our findings implicating PICK1 as a susceptibility gene for SZ are consistent with a role for D-serine in the disease.

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

“…It would be expected that this would reduce D-serine levels and produce NMDAR hypofunction. PICK1, a protein that interacts with serine racemase, has been identified as a risk gene for schizophrenia [141].…”

Aspartate racemase, generating neuronal D-aspartate, regulates adult neurogenesis

“…D-serine, an endogenous ligand for the glutamate-NMDA receptor, is formed by serine racemase, a pyridoxal 5′-phosphate (PLP)-dependent enzyme that converts L-serine to D-serine (1). Deletion of serine racemase alters NMDA receptor neurotransmission and long-term potentiation (2)(3)(4), and its disturbance has been implicated in schizophrenia (5)(6)(7). D-aspartate is present in selected neuronal populations in the brain as well as in neuroendocrine tissues, such as the catecholaminergic cells of the adrenal medulla, the anterior/posterior lobes of the pituitary gland, the pineal gland, and the testes (8)(9)(10).…”

The schizophrenic faces of PICK1

“…It revealed an association between a single nucleotide polymorphism (SNP), rs3952 in intron 3 of pick1, and the diagnosis of schizophrenia [11]. A second case-study of 200 unrelated Japanese schizophrenic patients and 200 age-matched Japanese normal controls found an association between an SNP, rs2076369 in intron 4 of pick1, and schizophrenia but only when using 'disorganized' schizophrenics [12]. Associations of lower magnitude might be expected if disease susceptibility results from the combined effect of several variants in a gene.…”

“…The pick1 gene is located on chromosome 22q13.1, which is a genetic locus that frequently links to schizophrenia [8,[11][12][13]. At the protein level, PICK1 has been studied extensively because of its role in regulating the cell biology and functional properties of several important neuronal proteins [14][15][16].…”