Novel mode of nitric oxide neurotransmission mediated via S-nitroso-cysteinyl-glycine.
S-nitroso-cysteinyl-glycine, a novel nitric oxide-adduct thiol compound, can be detected in the brain (2.3+/-0.6 pmol/mg protein), and released following stimulation of sensory afferents to the rat ventrobasal thalamus in vivo (resting conditions 17 nM; stimulation: 186 nM). Iontophoretic application of CysNOGly (20-80 nA) onto thalamic neurons in vivo resulted in enhancements of excitatory responses to either NMDA or AMPA (182+/-13.6% and 244+/-27.8% of control values, n = 15). CysNOGly enhanced responses to stimulation of vibrissal afferents to 132+/-2.2% (n = 7) of control values. In contrast, the dipeptide CysGly reduced responses of ventrobasal neurons to NMDA and AMPA (54+/-8.4% and 55+/-10.8% of control, n = 5). CysNOGly was also a potent activator of soluble guanylate cyclase in vitro. Moreover, we found that NMDA elevated CysNOGly levels in vitro and this stimulatory effect was reduced by inhibitors of the neuronal NO synthase and of the gamma-glutamyl transpeptidase, suggesting that production of NO and CysGly is a prelude to CysNOGly synthesis. These findings suggest that the nitrosothiol CysNOGly plays a role in synaptic transmission in the ventrobasal thalamus. We propose a novel synaptic buffering mechanism where S-nitroso-cysteinyl-glycine serves to restrict the locus of action of nitric oxide and so increase its local availability for target delivery. This could lead to a change in neuronal responses favouring sensory transmission similar to that seen in wakefulness or arousal in order to locally enhance transmission of persistent sensory stimuli.
Salt
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Department of Visual Science, Institute of Ophthalmology, University College London, London EC1V 9EL, UK. t.salt@ucl.ac.uk
Zhang
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Mayer
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Benz
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Do
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D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D002417:Cattle; D002531:Cerebellum / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000201:enzymology; D016202:N-Methylaspartate / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D010812:Physical Stimulation; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000494:pharmacology* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013788:Thalamus / Q000502:physiology*; D014738:Vibrissae / Q000294:innervation
D004151:Dipeptides; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C417091:S-nitrosocysteinylglycine; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; C028505:cysteinylglycine; D016202:N-Methylaspartate; D006162:Guanylate Cyclase