Nitric OxideWhat is Nitric Oxide?The structure and nature of Nitric OxideSynthesis of Nitric OxideActivation of NOSSlide 6Types of NOSWhat is the role of Nitric Oxide in the human body?Nitric Oxide in the Nervous SystemIs Nitric Oxide a “neurotransmitter?”Nitric Oxide in the Circulatory SystemNitric Oxide in the Muscular SystemSlide 13Nitric Oxide in the Immune SystemNitric Oxide in the Digestive SystemNew research ideas involving Nitric OxideReferencesSources on the World Wide WebNitric OxideNitric OxideBy Steven KnappChemistry 4124-12-99What is Nitric Oxide?What is Nitric Oxide?First described in 1979 as a potent relaxant of peripheral vascular smooth muscle. Used by the body as a signaling molecule.Serves different functions depending on body system. i.e. neurotransmitter, vasodilator, bactericide. Environmental PollutantFirst gas known to act as a biological messengerThe structure and nature of The structure and nature of Nitric OxideNitric OxideNitric oxide is a diatomic free radical consisting of one atom of nitrogen and one atom of oxygenLipid soluble and very small for easy passage between cell membranesShort lived, usually degraded or reacted within a few secondsThe natural form is a gasN OSynthesis of Nitric OxideNitric oxide is synthesized from L-arginine This reaction is catalyzed by nitric oxide synthase, a 1,294 aa enzymeCOO-C(CH2)3NHCH2NHNH2++H3NArginineNOSNADPH+ O2NAD+COO-C(CH2)3NHCH+H3NN+H2NHOHN-w-HydroxyarginineCOO-C(CH2)3NHH+H3N+NONOSCO NH2CitrullineActivation of NOSGlutamate neurotransmitter binds to NMDA receptorsCa++ channels open causing Ca influx into cellActivation of calmodulin, which activates NOSMechanism for start of synthesis dependent on body systemNO synthesis takes place in endothelial cells, lung cells, and neuronal cellsHttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.htmTypes of NOSNOS ICentral and peripheral neuronal cellsCa+2 dependent, used for neuronal communicationNOS IIMost nucleated cells, particularly macrophagesIndependent of intracellular Ca+2Inducible in presence of inflammatory cytokinesNOS IIIVascular endothelial cellsCa+2 dependentVascular regulationWhat is the role of Nitric What is the role of Nitric Oxide in the human body?Oxide in the human body?Nitric Oxide in the human body has many uses which are best summarized under five categories.NO in the nervous systemNO in the circulatory systemNO in the muscular systemNO in the immune systemNO in the digestive systemNitric Oxide in the Nervous Nitric Oxide in the Nervous SystemSystemNitric oxide as a neurotransmitterNO is a signaling molecule, but not necessarily a neurotransmitterNO signals inhibition of smooth muscle contraction, adaptive relaxation, and localized vasodilationNitric oxide believed to play a role in long term memoryMemory mechanism proposed is a retrograde messenger that facilitates long term potentiation of neurons (memory)Synthesis mechanism involving Ca/Calmodulin activates NOS-INO travels from postsynaptic neuron back to presynaptic neuron which activates guanylyl cyclase, the enzyme that catalyzes cGMP productionThis starts a cycle of nerve action potentials driven by NOIs Nitric Oxide a “neurotransmitter?”NO serves in the body as a neurotransmitter, but there are definite differences between other neurotransmitters used commonly in the bodyNO is synthesized on demand vs. constant synthesisNO diffuses out of the cells making it vs. storage in vesicles and release by exocytosisNO does not bind to surface receptors, but instead exits cytoplasm, enters the target cell, and binds with intracellular guanylyl cyclase Similarities to normal NTsPresent in presynaptic terminalNatural removal from synaptic junctionNitric Oxide in the Circulatory Nitric Oxide in the Circulatory SystemSystemNO serves as a vasodilatorReleased in response to high blood flow rate and signaling molecules (Ach and bradykinin)Highly localized and effects are briefIf NO synthesis is inhibited, blood pressure skyrockets(Diagram of vasodilation mechanism after muscular system)NO aids in gas exchange between hemoglobin and cellsHemoglobin is a vasoconstrictor, Fe scavenges NONO is protected by cysteine group when O2 binds to hemoglobinDuring O2 delivery, NO locally dilates blood vessels to aid in gas exchangeExcess NO is picked up by HGB with CO2Nitric Oxide in the Muscular Nitric Oxide in the Muscular SystemSystemNO was orginally called EDRF (endothelium derived relaxation factor)NO signals inhibition of smooth muscle contractionCa+2 is released from the vascular lumen activating NOSNO is synthesized from NOS III in vascular endothelial cellsThis causes guanylyl cyclase to produce cGMPA rise in cGMP causes Ca+2 pumps to be activated, thus reducing Ca+2 concentration in the cellThis causes muscle relaxationHttp://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-11.htmNitric Oxide in the Immune Nitric Oxide in the Immune SystemSystemNOS II catalyzes synthesis of NO used in host defense reactionsActivation of NOS II is independent of Ca+2 in the cellSynthesis of NO happens in most nucleated cells, particularly macrophagesNO is a potent inhibitor of viral replicationNO is a bactericidal agent NO is created from the nitrates extracted from food near the gumsThis kills bacteria in the mouth that may be harmful to the bodyNitric Oxide in the Digestive Nitric Oxide in the Digestive SystemSystemNO is used in adaptive relaxation NO promotes the stretching of the stomach in response to filling.When the stomach gets full, stretch receptors trigger smooth muscle relaxation through NO releasing neuronsNew research ideas involving New research ideas involving Nitric OxideNitric OxideThe role NO might play in neuronal developmentThe mechanism of NO inhibiting the different forms of NOSDiazeniumdiolates as NO releasing drugsExcessive NO release as the cause of most brain damage after strokeReferencesReferencesMarieb, Elaine N. Human Anatomy and Physiology. (1998) 4th ed. California, Benjamin/Cummings Science Publishing. 391, 826-27, 533, 859Stryer Lubert. Biochemistry. (1996) 4th ed. New York, W. H. Freeman and Company. 732Keefer, Larry K. “Nitric oxide-releasing compounds: From basic research to promising
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