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