Group I metabotropic glutamate receptors stimulate the activity of poly(ADP-ribose) polymerase in mammalian mGlu1-transfected cells and in cortical cell cultures

Abstract

Group I metabotropic glutamate (mGlu) receptors (i.e. mGlu1 and mGlu5) coupled to phospholipase C have been widely investigated for their possible role in excitotoxic and post-ischemic neuronal death. Recently, phospholipase C has been shown to directly stimulate the activity of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair that has been proposed to play a key role in necrotic cell death. In this study, we investigated whether the stimulation of group I mGlu receptors leads to an increase in PARP activity, as detected by flow cytometry, immunodot blot and immunocytochemistry, both in baby hamster kidney cells transfected with mGlu1a or mGlu5a receptors and in cultured cortical cells. Our results show that the group I mGlu receptor agonist DHPG elicited a significant increase in PARP activity that was completely abolished by the administration of the mGlu1 antagonist 3-MATIDA and partially prevented, in cortical neurons, by the mGlu5 antagonist MPEP. To evaluate whether this pathway is involved in post-ischemic neuronal death, we used a sublethal model of oxygen-glucose deprivation in mixed cortical cell cultures. DHPG exacerbated neuronal death, and this effect was significantly prevented by the application of the PARP inhibitor DPQ. This novel pathway may contribute to the effects of mGlu1 receptors in the mechanisms leading to post-ischemic neuronal death.

Post‐ischemic brain damage: targeting PARP‐1 within the ischemic neurovascular units as a realistic avenue to stroke treatment

“…The proposed molecular events underlying these observations include: overactivation of NMDA glutamate receptors with consequent intracellular Ca 2+ influx; and subsequent ROS production mainly caused by neuronal nitric oxide synthase activity, which, in turn, triggers DNA damage‐dependent hyperactivation of PARP‐1, depletion of intracellular NAD and ATP stores, and neuronal death [26]. PARP‐1 activation may also occur in neurons without NMDA receptor activation, as increases of intracellular [Ca 2+ ] triggered by K + ‐induced depolarization or inositol 3‐phosphate‐receptor activation are sufficient to trigger poly(ADP‐ribose) formation [28,64]. In keeping with this toxic cascade of events, neurons obtained from PARP‐1‐deficient mice are resistant to NMDA toxicity and to oxygen and glucose deprivation [65].…”

Mild activation of poly(ADP‐ribose) polymerase (PARP) is neuroprotective in rat hippocampal slice models of ischemic tolerance

“…, 1998; Mandir et al. , 2000) and DHPG (Meli et al. , 2005) can stimulate PARP activity, we sought to determine the role of this enzyme in the induction of ischemic tolerance in organotypic rat hippocampal slices exposed to OGD, an in vitro model of cerebral ischemia in use in our laboratory (Pellegrini‐Giampietro et al.…”

Interaction of Sindbis virus non-structural protein 3 with poly(ADP-ribose) polymerase 1 in neuronal cells

“…A number of alternative pathways for PARP-1 activation have been described. PARP-1 can be activated by binding to stem-loop DNA structures (Kun et al, 2002), by phosphorylation (Ju et al, 2004;Walker et al, 2006), by interaction with other proteins (Cohen-Armon et al, 2007;Griesenbeck et al, 1999;Kun et al, 2004) and by membrane depolarization followed by an increase in intracellular Ca 2+ (Homburg et al, 2000;Meli et al, 2005;Visochek et al, 2005). Membrane depolarization occurs in alphavirus-infected cells (Nargi-Aizenman & Griffin, 2001) and could potentially induce PARP activation.…”