Serine racemase: a key player in apoptosis and necrosis

Nadia Canu, Maria Teresa Ciotti, Loredano Pollegioni, Nadia Canu, Maria Teresa Ciotti, Loredano Pollegioni

Abstract

A fine balance between cell survival and cell death is required to sculpt the nervous system during development. However, an excess of cell death can occur following trauma, exposure to neurotoxins or alcohol, and some developmental and neurodegenerative diseases, such as Alzheimer's disease (AD). N-Methyl-D-aspartate receptors (NMDARs) support synaptic plasticity and survival of many neuronal populations whereas inappropriate activation may promote various forms of cell death, apoptosis, and necrosis representing the two extremes of a continuum of cell death processes both "in vitro" and "in vivo." Hence, by identifying the switches controlling pro-survival vs. apoptosis and apoptosis vs. pro-excitotoxic outcome of NMDAR stimulation, NMDAR modulators could be developed that selectively block the cell death enhancing pro-survival signaling or synaptic plasticity mediated by NMDAR. Among these modulators, a role is emerging for the enzyme serine racemase (SR) that synthesizes D-serine, a key co-agonist with glutamate at NMDAR. This review summarizes the experimental evidence from "in vitro" neuronal cultures-with special emphasis on cerebellar granule neurons (CGNs)-and "in vivo" models of neurodegeneration, where the dual role of the SR/D-serine pathway as a master regulator of apoptosis and the apoptosis-necrosis shift will be discussed.

Keywords: D-serine; NMDAR; apoptosis-necrosis shift; neurodegeneration; neurological disorders; review; serine racemase.

Figures

Figure 1
Figure 1
Reactions catalyzed by serine racemase: (A) racemization; (B) α, β-elimination. Lys56 of SR binds the PLP cofactor, forming an internal aldimine; then SR reacts with L-serine to yield an external aldimine; α-proton abstraction from this intermediate gives a resonance-stabilized carbanion. Two alternative pathways are possible starting from this intermediate (see text for details).
Figure 2
Figure 2
Scheme illustrating the main pro-survival and pro-death signals triggered by NMDAR activity.
Figure 3
Figure 3
Dimeric structure of human SR and details of the active site. PLP is shown in orange, malonate in red, and Mn2+ as red sphere.

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