Group I and group III metabotropic glutamate receptor subtypes provide enhanced neuroprotection

Neuroprotection by the metabotropic glutamate receptor (mGluR) system has been linked to the modulation of both the free radical nitric oxide (NO) and programmed cell death (PCD). Because the cellular mechanisms that ultimately determine neuronal PCD rely upon the independent pathways of genomic DNA degradation, externalization of membrane phosphatidylserine (PS) residues, and the activation of associated cysteine proteases, we investigated the ability of the individual mGluR subtypes to modulate the distinct pathways of NO-induced PCD in primary rat hippocampal neurons. Membrane PS residue externalization occurred within the initial 3 hr after exposure to the NO donors (300 microM SNP or 300 microM NOC-9), preceded genomic DNA fragmentation, and was present in 80 +/- 2% of the neurons within a 24-hr period. NO exposure also led to the rapid induction of both caspase 1-like and caspase 3-like activities that were determined to be necessary, at least in part, for the generation of NO-induced genomic DNA degradation, but distinct from the detrimental effects of intracellular acidification. Yet, only caspase 1-like activity was necessary for the modulation of PS residue externalization. Activation of group I mGluR subtypes utilized an effective, "upstream" mechanism for the inhibition of cysteine protease activity that offered an enhanced level of neuroprotection through both the preservation of genomic DNA integrity and the maintenance of PS membrane asymmetry. Group II and Group III mGluR subtypes maintained DNA integrity and group III mGluR subtypes additionally prevented PS residue externalization through mechanisms that were targeted below the level of caspase activation. Our work elucidates the independent nature of the mGluR subtypes to not only provide discrete levels of protection against neuronal PCD, but also offer robust therapeutic strategies for neurodegenerative disease.