medigraphic.com
ISSN 0185-3325 (Print)
Órgano Oficial del Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz

2003, Number 2

<< Back Next >>

Salud Mental 2003; 26 (2)

Aspectos sobre las funciones del óxido nítrico como mensajero celular en el sistema nervioso central

Talavera-Cuevas E, Condes-Lara M, Martínez-Lorenzana G

Language: Spanish
References: 54
Page: 42-50
PDF size: 425.41 Kb.


ABSTRACT

The discovery of nitric oxide (NO) in the last decade opened a new and important research field that has provided new insights on communication and regulation mechanisms taking place in different cellular populations, including animals and plants. In humans, this molecule participates in the physiology of almost all bodily systems such as cardiovascular, nervous, respiratory, and reproductive tracts. This means that alterations in its synthesis originate various pathological modifications, including hypertension, impotence, vascular complications, diabetes, asthma, and neurodegeneration.
In the nervous system, nitric oxide acts as a cellular messenger, and together with carbon monoxide forms the gaseous neurotransmitter family. It is considered an atypical neurotransmitter since it is not stored in synaptic vesicles. Once synthetized, it diffuses through the cellular membrane reaching different target molecules within a 40-100 μm radius, lacking a specific receptor molecule. One of its best known target molecules is guanylate cyclase, which is activated to produce the necessary cyclic GMP to relax blood vessels.
Among its properties is that of being a free radical, which means that it has an unpaired electron, making it highly reactive with other molecules such as the radicals superoxide, hemeproteins, thiol and amino groups, as well as oxygen. Thus, NO participates in various signaling mechanisms regulating the activity of several proteins and gene expression. Besides, NO can be released from nervous terminals, axons, and neuronal cell bodies.
In all cellular types of animal and plants where NO has been detected, it has been found that its precursor is the aminoacid Larginine, and its by-product is L-citrulline. The synthesis reaction takes place thanks to a family of isoenzymes known as nitric oxide synthases (NOS). These were named, depending on their isolation and cloning site, as endothelial, neuronal, and inducible. Although these enzymes have similar molecular characteristics, the synthetic activity of each one of them depends on various factors such as the NO amount produced on the tissue of the organ where the enzyme was found, the interaction with other molecules, and the role of NO in that tissue.
In neurons, NO synthesis is produced by a glutamic acid release that binds to NMDA receptors and/or metabotropic molecules activating Ca++ entrance into the cell, where this ion acts upon calmodulin molecules, which in turn bind to NO synthase oxidating its substrate, arginine, and producing both NO and the by-product citrulline. This post-synaptic synthetic mechanism and its presynaptic action producing the release of glutamic acid form a feedback loop that originated the hypothesis stating that NO is one of the molecules responsible for long term potentiation, one of memory storing mechanisms.
In its role as a free radical, NO produces direct and indirect effects upon reacting. The former are related to processes associated with cellular signaling mechanisms present in normal conditions such as guanylate cyclase activation to produce cGMP. On the other hand, indirect NO effects occur when this compound reacts with other molecules having activity per se, such as superoxide radicals (O2), which upon reaction originate peroxynitrite (ONOO-) capable of producing oxidative stress, cellular damage, and even death, when found in high concentrations. These NO effects are related to nitric oxide synthases, since endothelial and neuronal NOS produce NO in nanomolar concentrations, while inducible NOS synthesizes micromolar concentrations of this compound.
When a cerebral lesion or an infection is present, different molecules associated with inflammmatory processes are synthetized, such as cytokines, that are known to induce iNOS expression. This synthase is capable of originating high NO concentrations for long periods. Infections produced by hepatitis virus, choriomeningitis and AIDS virus activate iNOS expression in astrocytes. Similarly, this enzyme has been detected in glia in diseases such as Parkinson and Alzheimer, as well as in cerebral ischemia. However, it is not known whether NO could be a neurodegenerative agent or a protector of the nervous system, for although high NO concentrations originate indirect effects participating in oxidative stress, there is evidence showing that this molecule could be associated with neuroprotection.
Understanding of the NO synthetic pathway and the availability of different NO inhibitory or donating molecules, as well as studies carried out in mice lacking one of the NO synthases due to genetic manipulations, have provided information on the physiology of this cellular messenger on different bodily systems. Nevertheless, its effects on various nervous pathologies in which NO is associated have yet to be clarified. It is also necessary to have specific synthase inhibitors for each of the enzymes.
The aim of this paper is to review different aspects related to NO cellular physiology in the nervous system. Special emphasis will be drawn to its participation as an atypical cellular messenger, as well as regulation of NO synthesis by the three different synthases.
In addition, NO effects as a free radical, NO regulation on neurotransmitter release, and the interaction of this molecule with target proteins will be discussed. Finally, its role in neurodegenerative diseases will be briefly addressed.


REFERENCES

  1. BAUDRY M, LYNCH G: Hypothesis regarding the cellular mechanisms responsible for long-term synaptic potentiation in the hippocampus. Exp Neurol, 68:202-4, 1980.

  2. BELAI A, SCHMIDT HH, HOYLE CH, HASSALL CJ, SAFFREY MJ, MOSS J, FORSTERMANN U, MURAD F, BURNSTOCK G: Colocalization of nitric oxide synthase and NADPH-diaphorase in the myenteric plexus of the rat gut. Neurosci Lett, 143:60-4, 1992.

  3. BLISS T, COLLINGRIDE GL: A synaptic model of memory: long term potentiation in the hippocampus. Nature, 361:31-39, 1993.

  4. BOGDAN C: Nitric oxide and the regulation of gene expression. Trends Cell Biol, 11:66-75, 2001.

  5. BOUTON C, RAVEAU M, DRAPIER JC: Modulation of iron regulatory protein functions. Further roles of nitrogen and oxygen derived reactive species. J Biol Chem, 271:2300- 2306, 1996.

  6. BREDT DS, GLATT CE, HWANG PM, FOTUHI M, DAWSON TM, SNYDER SH: Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron, 7:615-24, 1991.

  7. BREDT DS, SNYDER SH: Isolation of nitric oxide synthetase a calmodulin-requiring enzyme. Proc Natl Acad Sci USA, 87:682-685, 1990.

  8. BROWN T, MCAFEE DA: Long-term synaptic potentiation in the superior cervical ganglion. Science, 215:1411-3, 1982.

  9. BRUNING G: Localization of NADPH diaphorase, a histochemical marker for nitric oxide synthase, in the mouse spinal cord. Acta Histochem, 93:397-401, 1992.

  10. CHABRIER P, AUGUET M, SPINNEWYN B, AUVIN S, CORNET S, DEMERLE-PALLARDY C, GUILMARDFAVRE C MJ, PIGNOL B, GILLARD-ROUBERT V, ROUSSILLOT-CHARNET C, SCHULZ J, VIOSSAT I, BIGG D, MONCADA S: BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy. Proc Natl Acad Sci USA, 96:10824-9, 1999.

  11. DESMOND N, LEVY WB: Changes in the numerical density of synaptic contacts with long-term potentiation in the hippocampal dentate gyrus.J Comp Neurol, 253:466-75, 1986.

  12. DIRNAGL U, LUNDAUER U, VILLRINGER A: Role of nitric oxide in the coupling of cerebral blood flow to neuronal activation in rats. Neurosci Lett, 149:43-6, 1993.

  13. DOUGLAS R, GODDARD GV: Long-term potentiation of the perforant path-granule cell synapse in the rat hippocampus. Brain Res, 86:205-15, 1975.

  14. DUMUIS A, PIN JP, OOMAGARI K, SEBBEN M, BOCKAERT J: Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature, 347:182-4, 1990.

  15. EDELMAN GM, GALLY JA: Nitric Oxide: Linking space and time in the brain. Proc Natl Acad Sci USA, 89:11651-11652, 1992.

  16. EGELMAN D, KING RD, MONTAGUE PR: Interactions of nitric oxide and external calcium fluctuations: A possible substrate for rapid information retrieval. En: Mize R, Dawson TM, Dawson VL, Friedlander MJ (eds). Progress in Brain Res. Elsevier Science, 199-211, Amsterdam, 1998.

  17. FENIK-MELODY J, BRUNNERT S, WEIDNER J, SHEN F, SHELTON B, MUDGETT JS:Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOSgene. J Immunol, 160:2940-2949, 1988.

  18. FERNANDEZ-GUARDIOLA A, CALVO JM, PELLICER F: Long-term Synaptic Potentiation and Burst Response Increment Could be due to Enkephalinergic Disinhibition. Experiments on the Spinal Cord and Amygdaloid Kindling. En: Juhn W (ed). Raven Press, 157-171, Nueva York, 1986.

  19. FURCHGOTT R, ZAWADZKI J: The role of endothelium in the responses of vascular smooth muscle to drugs. Ann Rev Pharmacol Toxicol, 24:175-179, 1984.

  20. GARTHWAITE J, BOULTON CL: Nitric oxide signaling in the central nervous system. Annu Rev Physiol, 57:683-706, 1995.

  21. HALEY J, WILCOX GL, CHAPMAN PF: The role of nitric oxide in hippocampal long-term potentiation. Neuron, 8:211-6, 1992.

  22. HAWKINS RD, SON H, ARANCIO O: Nitric oxide as a retrograde messenger during long-term potentiation in hippocampus. Prog Brain Res, 118:155-72, 1998.

  23. HEMMENS B, MAYER B: Enzymology of nitric oxide synthases. En: Titheradge MA (ed). Methods in Molecular Biology. Humana Press, 1-32, Totowa, 1998.

  24. HORI K BP, FURUKE K, KUTZA J, WEIH KA, CLOUSE KA: HIV-I infected macrophages induces iNOS and NO production in astrocytes. Blood, 93:1843-1850, 1999.

  25. IGNARRO L, BUGA GM, WOOD KS, BYRNS RE, CHAUDHURI G: Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA, 84:9265-9, 1987.

  26. KERWIN J, HELLER M: The Arginine-nitric oxide pathway: A target for new drugs. Med Res Rev, 14:23-74, 1994.

  27. LANE T, BUCHMEIER M, WATRY D, FOX HS: Expression of inflamatory cytokines and inducible nitric oxide synthase in brains of SIV-infected Rhesus monkeys:aplications to HIVinduced central nervous system disease. Mol Med, 2:27-37, 1996.

  28. LYNCH G, BROWNING M, BENNETT WF: Biochemical and physiological studies of long-term synaptic plasticity. Fed Proc, 38:2117-22, 1979.

  29. MENSHIKOVA E, ZENKOV NK, REUTOV VP: Nitric oxide and NO-synthases in mammals in different functional states. Biochemistry (Mosc), 65:409-26, 2000.

  30. MERRILL J, BENVENISTE EN:Citokines in inflamatory brain lesion: helpful and harmful. Trends Neurosci, 19:331-338,1996.

  31. MIRANDA K, ESPEY MG, JOURD HEUIL D, GRISHAM MB, FUKUTO JM FM, WINK DA: The Chemical Biology of Nitric Oxide. En: Ignarro LJ (ed). Academic Press, 41-55, Orlando, 2000.

  32. MONTAGUE P, GANCAYCO CD, WINN MJ, MARCHASE RB, FRIEDLANDER MJ: Role of NO production in NMDA receptor-mediated neurotransmitter release in cerebral cortex. Science, 263:973-7, 1994.

  33. MURPHY S: Production of nitric oxide by glial cells. Glia, 29:1-4, 2000.

  34. NOWICKY A, BINDMAN LJ: The nitric oxide synthase inhibitor, N-monomethyl-L-arginine blocks induction of a long-term potentiation-like phenomenon in rat medial frontal cortical neurons in vitro. J Neurophyol, 70:1255-9, 1993.

  35. O´DELL T, HUANG PL, DAWSON TM, DINERMAN JL, SNYDER SH, KANDEL ER, FISHMAN MC: Endothelial NOS and the blockade of LTP by NOS inhibitors in mice lacking neuronal NOS. Science, 265:542-6, 1994.

  36. OHKUMA S, MASASHI K: Nitric oxide and peroxynitrite as factor to stimulate neurotransmitter release in the CNS. Progress Neurobiol, 64:97-108, 2001.

  37. OKUDA Y, FUJIMARA H, YANAGIHARA T: NO via and inducible isoform of NOS is a possible factor to eliminate inflamatory cells from the CNS of mice with EAE. J Immunol, 73:107-116, 1977.

  38. PALMER R, ASHTON D, MONCADA S: Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature, 333:664-666, 1988.

  39. PALMER R, FERRIGE AG, MONCADA S: Nitric oxide release accounts for the biological activity of endotheliumderived relaxing factor. Nature, 327:524-6, 1987.

  40. PETROV T, PAGE AB, OWEN CR, RAFOLS JA: Expression of the inducible nitric oxide synthase in distinct cellular types after traumatic brain injury: An in situ hybridization and immunocytochemical study. Acta Neuropathol (Berl), 100:196- 204, 2000.

  41. POSSEL H, NOACK H, PUTZKE J, WOLF G, SIES H: Selective upregulation of inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS) and cytokines in microglia: in vitro and in vivo studies. Glia, 32:51-9, 2000.

  42. RADOMSKI M, PALMER RM, MONCADA S:Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet, 2:1057-8, 1987.

  43. RAND M, LI CG: Nitric oxide as a neurotransmitter in peripheral nerves: nature of transmitter and mechanism of transmission. Annu Rev Physiol, 57:659-82, 1995.

  44. SANCHEZ-ALVAREZ M, LEON-OLEA M, TALAVERA E, PELLICER F, SANCHEZ-ISLAS E, MARTINEZ-LORENZANA G: Distribution of NADPH-diaphorase in the perioesophageal ganglia of the snail, Helix aspersa. Neurosci Lett, 169:51-55, 1994.

  45. SCHMIDT H, SMITH RM, NAKANE M, MURAD F:Ca/ Calmodulin-dependent NO synthase type I: A biopteroflavoprotein with Ca++/calmodulin-independent diaphorase and reductase activities. Biochemistry, 31:3243-3249, 1992.

  46. SCHUMAN E, MADISON DV: Locally distributed synaptic potentiation in the hippocampus. Science, 263:532-6, 1994.

  47. SON H, HAWKINS RD, MARTIN K, KIEBLER M, HUANG PL, FISHMAN MC, KANDEL ER: Long-term potentiation is reduced in mice that are doubly mutant in endothelial and neuronal nitric oxide synthase. Cell, 87:1015- 23, 1996.

  48. STUEHR D, POU S, ROSEN GM: Oxygen reduction by nitric-oxide synthases. J Biol Chem, 276:14533-6, 2001.

  49. STUEHR DJ: Structure-function aspects in the nitric oxide synthases. Annu Rev Pharmacol Toxicol, 37:339-59, 1997.

  50. TALAVERA E, MARTINEZ-LORENZANA G, LEONOLEA M, SANCHEZ-ALVAREZ M, SANCHEZ-ISLAS E, PELLICER F: Histochemical distribution of NADPHdiaphorase in the cerebral ganglion of crayfish Cambarellus montezumae. Neurosci Lett, 187:177-180, 1995.

  51. VINCENT S, KIMURA H: Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience, 46:755-84, 1992.

  52. WENDEHENNE D, PUGIN A, KLESSIG DF, DURNER J: Nitric oxide: comparative synthesis and signaling in animal and plant cells. Trends Plant Sci, 6:177-83, 2001.

  53. WHITE R, VALLANCE P, MARKUS HS: Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans. Clin Sci, 99:555-60, 2000.

  54. ZHAO Y, BRANDISH PE, BALLOU PD, MARLETTA MA: A molecular basis for nitric oxide sensing by soluble guanylate cyclase. Proc Natl Acad Sci, 96:14753-14758, 1999.




2020     |     www.medigraphic.com