Nuclear Compartmentalization of Serine Racemase Regulates d-Serine Production

Abstract

D-Serine is a physiological co-agonist that activates N-methyl D-aspartate receptors (NMDARs) and is essential for neurotransmission, synaptic plasticity, and behavior. D-Serine may also trigger NMDAR-mediated neurotoxicity, and its dysregulation may play a role in neurodegeneration. D-Serine is synthesized by the enzyme serine racemase (SR), which directly converts L-serine to D-serine. However, many aspects concerning the regulation of D-serine production under physiological and pathological conditions remain to be elucidated. Here, we investigate possible mechanisms regulating the synthesis of D-serine by SR in paradigms relevant to neurotoxicity. We report that SR undergoes nucleocytoplasmic shuttling and that this process is dysregulated by several insults leading to neuronal death, typically by apoptotic stimuli. Cell death induction promotes nuclear accumulation of SR, in parallel with the nuclear translocation of GAPDH and Siah proteins at an early stage of the cell death process. Mutations in putative SR nuclear export signals (NESs) elicit SR nuclear accumulation and its depletion from the cytosol. Following apoptotic insult, SR associates with nuclear GAPDH along with other nuclear components, and this is accompanied by complete inactivation of the enzyme. As a result, extracellular D-serine concentration is reduced, even though extracellular glutamate concentration increases severalfold. Our observations imply that nuclear translocation of SR provides a fail-safe mechanism to prevent or limit secondary NMDAR-mediated toxicity in nearby synapses.

Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging

“…An increase in SR activity, due to activation or the prevention of its degradation, may be promoted by the small ligands ATP and Mg 2+ (De Miranda et al, 2002 ; Strísovský et al, 2003 ; Foltyn et al, 2005 ), multiple protein interactors including GRIP, Golga3, Disc-1 and FBXO22 (Kim et al, 2005 ; Dumin et al, 2006 ; Ma et al, 2013 ; Dikopoltsev et al, 2014 ), by O-palmitoylation-related processes (Balan et al, 2009 ) and also possibly through phosphorylation at different residues (Balan et al, 2009 ; Foltyn et al, 2010 ). On the other hand, nicotinamide adeninedinucleotide (NADH) (Suzuki et al, 2015 ; Bruno et al, 2016 ), protein interactions with Pick-1 (Fujii et al, 2006 ), PSD-95 (Ma et al, 2014 ; Lin et al, 2016 ), SAP102 and stargazin (Ma et al, 2014 ), membrane or nuclear translocations (Balan et al, 2009 ; Kolodney et al, 2015 ) and S-Nitrosylation-related oxidative processes (Mustafa et al, 2007 ) inhibit SR activity. Therefore, the SR activity itself appears to be modulated in a complex manner by a large mosaic of mechanisms, which can be targeted by the aging process.…”