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Electronic Letters to:
- DevelopmentPlasticityRepair:
Helene Girouard, Gang Wang, Eduardo F. Gallo, Josef Anrather, Ping Zhou, Virginia M. Pickel, and Costantino Iadecola- NMDA Receptor Activation Increases Free Radical Production through Nitric Oxide and NOX2
J. Neurosci. 2009; 29: 2545-2552[Abstract] [Full text] [PDF]
eLetters: Submit a response to this article
Electronic letters published:
Is the protection by tat-NR2B9c through partially reducing the ROS generation after stroke?
- Rao M Adibhatla (16 March 2009)
- Costantino Iadecola, Eduardo F. Gallo, Josef Anrather (20 March 2009)
Is the protection by tat-NR2B9c through partially reducing the ROS generation after stroke? 16 March 2009 
Rao M Adibhatla,
Assistant Professor
University of Wisconsin School of Medicine and Public Health, Madison, WI53792Send letter to journal:
Re: Is the protection by tat-NR2B9c through partially reducing the ROS generation after stroke?
adibhatl{at}neurosurg.wisc.edu Rao M Adibhatla
I read with interest the article by Girouard et al (Girouard et al., 2009) that NMDA receptor activation increases free radical production, and tat-NR2B9C peptide dissociated the interaction between nNOS and NR2 and subsequently reduced the ROS generation by NMDA. TAT-NR2B9C (a postsynaptic density-95, PSD-95 inhibitor) offered neuroprotection both in in vitro and in tMCAO models (Aarts et al., 2002). Liu et al (Liu et al., 2007) showed a dual role of NMDA receptors (either synaptic or extrasynaptic) promoting neuronal survival (by NR2A subunit) and mediating neuronal death through excitotoxicity (by NR2B subunit). In this connection, it is interesting to note that reducing ROS generation by tat- NR2b9C (Girouard et al., 2009) may offer an additional layer of protection in stroke models (Aarts et al., 2002; Sun et al., 2008).
A point for clarification is requested: Towards the conclusions Girouard et al (2009) suggest “These novel findings demonstrate that NADPH oxidase, colocalized post-synaptically with nNOS and NR1, is a major source of ROS generated……”. Tat-NR2B9c (0.2 – 8 microM) inhibits interaction of PSD-95 with other NMDA receptor subunits NR2A, 2B, and 2C, but does have higher affinity for blocking PSD-95/nNOS interaction (Cui et al., 2007). Are there any additional data that supports NR1 alone regulates nNOS? Does nNOS couple to NMDA receptor through NR2A, B, or C, or NR1 only?
Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang Y-T, Salter MW, Tymianski M (2002) Treatment of ischemic brain damage by pertubing NMDA receptor-PSD-95 protein interactions. Science 298:846-850.
Cui H, Hayashi A, Sun H-S, Belmares MP, Cobey C, Phan T, Schweizer J, Salter MW, Wang YT, Tasker RA, Garman D, Rabinowitz J, Lu PS, Tymianski M (2007) PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J Neurosci 27:9901-9915.
Girouard H, Wang G, Gallo EF, Anrather J, Zhou P, Pickel VM, Iadecola C (2009) NMDA receptor activation increases free radical production through nitric oxide and NOX2. J Neurosci 29:2545-2552.
Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27:2846-2857.
Sun H-S, Doucette TA, Liu Y, Fang Y, Teves L, Aarts M, Ryan CL, Bernard PB, Lau A, Forder JP, Salter MW, Wang YT, Tasker RA, Tymianski M (2008) Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 39:2544-2553.
Re: Is the protection by tat-NR2B9c through partially reducing the ROS generation after stroke? 20 March 2009 
Costantino Iadecola,
Professor
Weill Cornell Medical College,
Eduardo F. Gallo, Josef AnratherSend letter to journal:
Re: Re: Is the protection by tat-NR2B9c through partially reducing the ROS generation after stroke?
coi2001{at}med.cornell.edu Costantino Iadecola, et al.
We thank Dr. Adibhatla for the interest in our paper. As for the clarification requested, the NMDA receptor is a tetramer formed by two NR1 and two NR2 subunits (Nat Rev Neurosci. 2007;8:413-426). There is no described direct association between NR1 and PSD-95. On the other hand, PSD-95 interacts with all NR2 isotypes and is likely the link between NMDA receptors and nNOS (J Biol Chem. 1999;274:27467-27473). The statement referred to in the letter, reflects our ultrastructural data demonstrating colocalization of NR1 (in our case used as a NMDAR marker), NOX2 and nNOS immunoreactivity at postsynaptic sites, and does not imply direct structural or functional interactions between NR1 and nNOS. We hope that this answers the question.
Sincerely,
C. Iadecola, E.F. Gallo, and J. Anrather, on behalf of the authors
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