Nuclear Compartmentalization of Serine Racemase Regulates d-Serine Production IMPLICATIONS FOR N-METHYL-d-ASPARTATE (NMDA) RECEPTOR ACTIVATION
2015
Abstract d-
Serineis a physiological co-agonist that activates N-methyl d-aspartate receptors (NMDARs) and is essential for neurotransmission, synaptic plasticity, and behavior. d-
Serinemay also trigger NMDAR-mediated neurotoxicity, and its dysregulation may play a role in neurodegeneration. d-
Serineis synthesized by the enzyme
serine racemase(SR), which directly converts l-
serineto d-
serine. However, many aspects concerning the regulation of d-
serineproduction under physiological and pathological conditions remain to be elucidated. Here, we investigate possible mechanisms regulating the synthesis of d-
serineby 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-
serineconcentration is reduced, even though extracellular glutamate concentration increases severalfold. Our observations imply that nuclear translocation of SR provides a
fail-safemechanism to prevent or limit secondary NMDAR-mediated toxicity in nearby synapses.
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