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Nitric Oxide Signaling

Nitric Oxide Signaling. LISC 414 January 12, 2004 Dr. J.N. Reynolds. History. 1980’s Endothelium Derived Relaxing Factor (EDRF) 1987 EDRF identified as Nitric Oxide (NO) 1992 NO “Molecule of the Year” 1998 Nobel Prize in Medicine Robert Furchgott Louis Ignarro Ferid Murad.

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Nitric Oxide Signaling

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  1. Nitric Oxide Signaling LISC 414 January 12, 2004 Dr. J.N. Reynolds

  2. History • 1980’s Endothelium Derived Relaxing Factor (EDRF) • 1987 EDRF identified as Nitric Oxide (NO) • 1992 NO “Molecule of the Year” • 1998 Nobel Prize in Medicine • Robert Furchgott • Louis Ignarro • Ferid Murad

  3. NO Synthase • NOS I (neuronal NOS, nNOS) • NOS II (inducible NOS, iNOS) • NOS III (endothelial NOS, eNOS)

  4. Biosynthesis of NO NOS catalyzes the oxidation of the guanidino group of L-arginine, leading to the equimolar formation of NO and L-citrulline, in a reaction that utilizes five electrons

  5. NOS I and NMDA Receptors • NOS I activation is tightly • coupled to NMDA receptor • activation by scaffolding proteins • such as PSD95 • NO production can serve as a • local marker for excitatory • glutamate-mediated • neurotransmission • - regulate local blood flow • recruitment of local circuit • neurons

  6. NO and Glutamate Release NO acts as a retrograde messenger molecule to regulate presynaptic glutamate release

  7. Physiological Effects of NO • NO activates soluble guanylyl cyclase to produce cGMP • cGMP activates CGCs to increase Ca2+ in presynaptic terminals • cGMP activates protein kinase G (PKG) • cGMP regulates phosphodiesterase activity • NO directly affects neurotransmitter release • NO helps regulate cerebrovascular blood flow

  8. NO and Neurodegeneration NO can give rise to reactive nitrogen species such as peroxynitrite (ONOO-). Peroxynitrite can act as a cytotoxic agent, damaging membrane structures and DNA. Sources for excess NO NMDA receptor-mediated excitotoxicity Microglial activation

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