Arginine metabolism and the synthesis of nitric oxide in the nervous system

doi:10.1016/S0301-0082(00)00056-3

Progress in Neurobiology

Volume 64, Issue 4, July 2001, Pages 365-391

https://doi.org/10.1016/S0301-0082(00)00056-3 Get rights and content

Abstract

The biochemistry and physiology of l-arginine have to be reconsidered in the light of the recent discovery that the amino acid is the only substrate of all isoforms of nitric oxide synthase (NOS). Generation of nitric oxide, NO, a versatile molecule in signaling processes and unspecific immune defense, is intertwined with synthesis, catabolism and transport of arginine which thus ultimately participates in the regulation of a fine-tuned balance between normal and pathophysiological consequences of NO production. The complex composition of the brain at the cellular level is reflected in a complex differential distribution of the enzymes of arginine metabolism. Argininosuccinate synthetase (ASS) and argininosuccinate lyase which together can recycle the NOS coproduct l-citrulline to l-arginine are expressed constitutively in neurons, but hardly colocalize with each other or with NOS in the same neuron. Therefore, trafficking of citrulline and arginine between neurons necessitates transport capacities in these cells which are fulfilled by well-described carriers for cationic and neutral amino acids. The mechanism of intercellular exchange of argininosuccinate, a prerequisite also for its proposed function as a neuromodulator, remains to be elucidated. In cultured astrocytes transcription and protein expression of arginine transport system y⁺ and of ASS are upregulated concomittantly with immunostimulant-mediated induction of NOS-2. In vivo ASS-immunoreactivity was found in microglial cells in a rat model of brain inflammation and in neurons and glial cells in the brains of Alzheimer patients. Any attempt to estimate the contributions of arginine transport and synthesis to substrate supply for NOS has to consider competition for arginine between NOS and arginase, the latter enzyme being expressed as mitochondrial isoform II in nervous tissue. Generation of NOS inhibitors agmatine and methylarginines is documented for the nervous system. Suboptimal supply of NOS with arginine leads to production of detrimental peroxynitrite which may result in neuronal cell death. Data have been gathered recently which point to a particular role of astrocytes in neural arginine metabolism. Arginine appears to be accumulated in astroglial cells and can be released after stimulation with a variety of signals. It is proposed that an intercellular citrulline–NO cycle is operating in brain with astrocytes storing arginine for the benefit of neighbouring cells in need of the amino acid for a proper synthesis of NO.

Section snippets

Introduction and scope of the review

The biochemistry and physiology of the amino acid l-arginine (also ‘arginine’ in the following) has been a field of active research for many years and a plethora of data on the metabolism and function of this amino acid has been gathered in the basic and clinical sciences. However, the recent discovery of the many diverse biological functions of nitric oxide, NO, shed new light on the role of arginine, which is the only physiologically significant substrate for NO synthesis. In the nervous

Arginine in mammals: an overview

Arginine has been classified as a ‘semi-essential’ or ‘conditionally essential’ amino acid. This characterization alludes to the fact that arginine has to be extracted from the diet (i.e. is an ‘essential’ amino acid) as a supplement to the endogenous synthesis in growing mammals and in adult animals or humans during disease or trauma; however, arginine can be synthezised in sufficient quantity in the healthy adult (Rose, 1937, Barbul, 1986). Nevertheless, even in the adult mammal not every

Arginine and NO

Arginine is substrate of all isoforms of NO synthase which generates from l-arginine and molecular oxygen NO and l-citrulline in a five-electron transfer reaction (Fig. 2). Moreover, it seems that arginine is the only physiological substrate for the generation of NO in eucaryotic cells, and arginine analogues are potent inhibitors of NOS (Grant et al., 1998). Thus the (patho-)physiologicol roles of arginine (Section 2.3) are intertwined with the biological effects of NO (Morris, 1999), and many

NO in the nervous system

In order to lay the grounds for a discussion of the role of arginine in the regulation of neural NO synthesis a concise overview of NO in the nervous system will be provided first. Several seminal papers will be referenced, however, in general the reader is referred to recent summaries. Since the present review is focussed on the CNS, it shall only be mentioned in passing that NOS appears to be wide-spread in the peripheral nervous system (e.g. Grozdanovic et al., 1992); at the functional

Arginine in the brain

Most features of arginine metabolism outlined above (see 2 Arginine in mammals: an overview, 3 Arginine and NO) are encountered when turning the attention to nervous tissue and the brain in particular. However, until recently a lack of data was obvious as soon as individual neural cell populations were focussed upon. The complex peripheral inter-organ cooperation may have its counterpart in a similarly complex intercellular cooperation within the one organ brain, and a fine-tuned ‘teamwork’

Concluding remarks

The renewed interest in arginine after the discovery of its role in the synthesis of the biologically important signaling and effector molecule NO is reflected in a renaissance of studies on metabolism and transport of the amino acid in the nervous system. However, experimental approaches to elucidate the interplay between arginine and generation of NO in nervous tissue are hampered by the complex cellular composition particularly of the brain. As a consequence, many results on the role of

Acknowledgements

The author is indebted to Dr R. Dringen, Tübingen, for critical reading of the manuscript, and wants to express his thanks to Drs T. Ogawa, now Kyoto University, Japan, and M. Kimoto, now Okayama University, Japan, for their generous gift of monoclonal antibody against DDAH. The author's own work was financially supported by the Deutsche Forschungsgemeinschaft (grants Wi 657/4-1 to 4-4) and the Fonds der Chemischen Industrie which is gratefully acknowledged.

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Arginine metabolism and the synthesis of nitric oxide in the nervous system

Abstract

Section snippets

Introduction and scope of the review

Arginine in mammals: an overview

Arginine and NO

NO in the nervous system

Arginine in the brain

Concluding remarks

Acknowledgements

Brain Res.

Neuroscience

Biochem. Biophys. Res. Commun.

Prog. Neurobiol.

Mol. Brain Res.

Neurosci. Lett.

Neuron

Cell

FEBS Lett.

FEBS Lett.

J. Biol. Chem.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Nitric Oxide

J. Biol. Chem.

J. Biol. Chem.

Neuroscience

Neurochem. Int.

Neurosci. Lett.

Neuroscience

Neuroscience

Neurosci. Lett.

J. Invest. Dermatol.

Eur. J. Pharmacol.

Neurosci. Lett.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Biochem. Biophys. Res. Commun.

Neuroscience

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Brain Res.

Biochim. Biophys. Acta

On the expression of nitric oxide synthase by human macrophages. Why no NO?

J. Leucoc. Biol.

Arginine metabolism in wounds

Am. J. Physiol.

The characteristics of arginine transport by rat cerebellar and cortical synaptosomes

Neurochem. Res.

Evidence for the presence of l-arginine in the glial components of the peripheral nervous system

Brain Res.

Characteristics of nitric oxide synthase type-I in rat cerebellar astrocytes

Glia

Arginine: biochemistry, physiology, and therapeutic implications

J. Parent. Ent. Nutr.

Discrimination between citrulline and arginine transport in activated murine macrophages: inefficient synthesis of NO from recycling of citrulline to arginine

Br. J. Pharmacol.

Transmembrane signalling mechanisms regulating expression of cationic amino acid transporters and inducible nitric oxide synthase in rat vascular smooth muscle cells

Biochem. J.

Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly

Am. J. Physiol.

Distribution of mRNA for the facilitated urea transporter UT3 in the rat nervous system

Anat. Embryol.

Histochemistry of nitric oxide synthase in the nervous system

Histochem. J.

l-Arginine transport is increased in macrophages generating nitric oxide

Biochem. J.

Induction of NG-monomethyl-l-arginine uptake: a mechanism for differential inhibition of NO synthases?

Am. J. Physiol.

Argininosuccinate lyase: generation of antisera against peptide sequences of the rat brain enzyme and immunochemical studies on glial cells

Biol. Chem.

Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for l-arginine utilization

Cell. Mol. Life Sci.

Localization of nitric oxide synthase indicating a neural role for nitric oxide

Nature

The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine.

Biochem. J.

Induction of N^G-monomethyl-l-arginine uptake: a mechanism for differential inhibition of NO synthases?