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Nitric Oxide: Biological Synthesis and Functions

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Gasotransmitters: Physiology and Pathophysiology

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Abstract

The pluripotent gaseous messenger molecule nitric oxide (NO) controls vital functions such as neurotransmission or vascular tone (via activation of soluble guanylyl cyclase), gene transcription, mRNA translation (via iron-responsive elements), and post-translational modifications of proteins (via ADP-ribosylation). In higher concentrations, NO is capable of destroying parasites and tumor cells by inhibiting iron-containing enzymes or directly interacting with the DNA of these cells. In view of this multitude of functions of NO, it is important to understand the mechanisms by which cells accomplish and regulate the production of this molecule. In mammals, three isozymes of NO synthase (NOS; L-arginine, NADPH:oxygen oxidoreductases, nitric oxide forming; EC 1.14.13.39) have been identified. These isoforms are referred to as neuronal “n”NOS (or NOS I), inducible “i”NOS (or NOS II), and endothelial “e”NOS (or NOS III). In pathophysiology, massive amounts of NO produced by hyperactive nNOS or highly expressed iNOS can contribute to processes such as neurodegeneration, inflammation, and tissue damage. This chapter will describe principles of NO biosynthesis, regulatory mechanisms controlling the production of this molecule, and the large array of (physiologic and pathophysiologic) functions that Mother Nature has assigned to this small messenger molecule.

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Abbreviations

AMP:

Adenosine monophosphate

ADMA:

Asymmetric dimethyl-L-arginine

ADP:

Adenosine diphosphate

Ala:

Alanine

Akt:

Serine/threonine kinase (= protein kinase B)

AMPK:

AMP-activated protein kinase

Asp:

Aspartate

AVE9488:

4-fluoro-N-indan-2-yl-benzamide (eNOS expression enhancer)

BH2 :

Quinonoid 6,7-[8H]-H2-biopterin

BH3 . :

Trihydrobiopterin radical

BH3 .H+ :

Trihydropterin radical cation protonated at N5

BH4 :

(6R)-5,6,7,8-tetrahydro-L-biopterin

CAPON:

Carboxy-terminal PDZ ligand of nNOS

CaM:

Calmodulin

CaMK:

Ca2+/Calmodulin-dependent protein kinase

cyclic GMP:

Cyclic guanosine monophosphate

DDAH:

Dimethylarginine dimethylaminohydrolase

Dexras1:

A small monomeric G protein found predominantly in brain

eNOS:

Endothelial nitric oxide synthase

FAD:

Flavin adenine dinucleotide

FMN:

Flavin mononucleotide

GLGF:

Glycine, leucine, glycine, phenylalanine motif

H2O2 :

Hydrogen peroxide

hsp90:

Heat shock protein 90

hsp70:

Heat shock protein 70

iNOS:

Inducible nitric oxide synthase

LLC-PK1 :

Porcine kidney tubular epithelial cells

L-NMMA:

NG-monomethyl-L-arginine

LPS:

Bacterial lipopolysaccharide

mRNA:

Messenger ribonucleic acid

NAP110:

NOS-associated protein 110 kDa

NADPH:

Reduced nicotinamide adenine dinucleotide phosphate

NMDA:

N-methyl-D-aspartate

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOSIP:

Nitric oxide synthase interacting protein

O −.2 :

Superoxide anion

ONOO− :

Peroxynitrite

PARP:

Poly(ADP-ribose)polymerase

PDZ:

Postsynaptic density protein 95/discs large/ZO-1 homology domain

PIN:

Protein inhibitor of nNOS

PFK-M:

Phosphofructokinase (muscle type)

PKA:

Protein kinase A

PKC:

Protein kinase C

PRMT:

Protein arginine N-methyltransferase

Ser:

Serine

SMTC:

S-methyl-L-thiocitrulline (inhibitor of nNOS)

ROS:

Reactive oxygen species

Thr:

Threonine

Tyr:

Tyrosine

VEGF:

Vascular endothelial growth factor

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Acknowledgments

Work from our laboratory mentioned in this chapter has been made possible by the Collaborative Research Center (Sonderforschungsbereich) 553 (Project A1 to H.L. and U.F.) and by Individual Grant LI-1042/1-1 from the German Research Foundation (Deutsche Forschungsgemeinschaft), and by the Integrated Research and Treatment Center “Thrombosis and Hemostasis” of the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF 01EO1003).

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  1. Department of Pharmacology, Johannes Gutenberg University Medical Center, Obere Zahlbacher Strasse 67, 55101, Mainz, Germany

    Ulrich Förstermann & Huige Li

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  1. Ulrich Förstermann
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  2. Huige Li
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Correspondence to Ulrich Förstermann .

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  1. , Department of Cell Biology, University of Salzburg, Heilbrunnerstr. 34, Salzburg, 5020, Austria

    Anton Hermann

  2. , Department of Human and Animal Physiolog, Kazan Federal University, ul. Kremlevskaya 18, Kazan, 420008, Russia

    Guzel F. Sitdikova

  3. , Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, Salzburg, 5020, Austria

    Thomas M. Weiger

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Förstermann, U., Li, H. (2012). Nitric Oxide: Biological Synthesis and Functions. In: Hermann, A., Sitdikova, G., Weiger, T. (eds) Gasotransmitters: Physiology and Pathophysiology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30338-8_1

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