The gaseous signalling molecule nitric oxide (NO) is and it has an important role in the peristalsis of the
among a number of molecules that have both autocrine gastrointestinal tract5,6.
and paracrine activities. During the past 20 years, thou NO is able to interact with many intracellular targets to
sands of papers have appeared in the literature unravel trigger an array of signal transduction pathways, resulting
ling the biological functions of NO, thus contributing in stimulatory or inhibitory output signals. Apart from the
to NO being named Molecule of the Year in 1992. In above mentioned physiological functions, NO becomes
1998, the importance of NO in the life sciences was noxious if it is produced in excess7; furthermore, if a cell
finally underscored when the Nobel Prize for Physiology is in a pro-oxidant state, NO can undergo oxidative
and Medicine was awarded to Robert Furchgott, reductive reactions to form toxic compounds (these
Louis Ignarro and Ferid Murad for their significant belong to a family known as reactive nitrogen species,
contributions to this field. or RNS), which cause cellular damage1,7. Recently, the
NO is produced from the amino acid larginine term nitrosative stress has been used to indicate the
by the members of the NO synthase (NOS) family of cellular damage that is elicited by excess NO and RNS
*Department of Chemistry,
Biochemistry and Molecular proteins, and is involved in several cellular functions, (mainly peroxynitrite and nitrogen (III) oxide)8,9, and
Biology Section, including neurotransmission, regulation of blood-vessel NO and RNS have been implicated in the pathogenesis
Faculty of Medicine, tone and the immune response. Different members of of neurodegenerative disorders1,10,11. In fact, some of the
University of Catania, the NOS family are known to regulate different func initial studies carried out on NO led to the hypothesis
Catania, Italy.
Institute of Pharmacology
tions. In the CNS, NO production is associated with that peroxynitrite, formed by the reaction between NO
and Department of Internal cognitive function, its role spanning from the induction and a superoxide anion, might be responsible for the cel
Medicine, Catholic University and maintenance of synaptic plasticity to the control of lular damage in neurodegenerative disorders; this con
School of Medicine, Roma, sleep, appetite, body temperature and neurosecretion13 cept brings together oxidative stress and nitrosative stress
Italy.
(FIG.1). In the PNS, NO regulates the non-adrenergic, and is a widely accepted explanation for the contribution
||
Department of Chemistry,
Sanders-Brown Center on non-cholinergic relaxation of smooth muscle cells. This of nitrosative stress to Alzheimers disease1,7.
Aging and Center of has consequences for a number of tissues: smooth- Given the broad range of functions of NO, we con
Membrane Sciences, muscle relaxation in the corpora cavernosa promotes centrate in this Review on both the physiological and
University of Kentucky, penile erection4 (FIG.1); NO also allows the stomach to pathological implications of NO activity in the regula
Lexington, Kentucky, USA.
Correspondence to V.C.
accommodate a large volume of ingested food with tion of the CNS. In particular, we focus our attention on
e-mail: calabres@unict.it out any significant increase in intraluminal pressure; the multifaceted functions of NO as a neuromodulator,
doi:10.1038/nrn2214 it regulates the muscle tone of intestinal sphincters; a neuroprotective and a neurotoxic agent.
Neurotransmission Levels of iNOS in the CNS are low, but iNOS can be
Regulation of food intake induced in astrocytes or microglial cells following events
Control of the sleepwake cycle such as inflammation, viral infection or trauma12,19.
Central effects Modulation of hormone release
Thermal regulation
NO in the Neuroprotection Nitric oxide signalling
nervous system Neurotoxicity Initial studies into NOmediated signalling indicated that
this gas interacts with soluble guanylyl cyclase (sGC) and
Control of smooth-muscle relaxation stimulates its activity (FIG.3). The consequent increase in
Peripheral effects Gastrointestinal tract intracellular levels of cyclic GMP can influence synaptic
Urogenital tract
plasticity, smooth-muscle relaxation, neurosecretion
Figure 1 | Nitric oxide in the CNS and PNS. The gaseous signalling molecule nitric and neurotransmission2225. NO has subsequently been
oxide (NO) is able to mediate several processes in the CNS and PNS. shown to interact with members of the haemoprotein
Nature Reviews | Neuroscience
family, such as cyclooxygenase26 and haem oxygenase 1
(REF. 27). This family of proteins is involved in metabolic,
The nitric oxide synthase family inflammatory and cellular stress responses.
The NOS family of enzymes is responsible for the synthesis NO also regulates the Akt kinase pathway and the
of NO; in the presence of oxygen, these enzymes catalyse transcription factor cyclic-AMP-responsive-element-
the conversion of larginine to lcitrulline plus NO binding protein (CREB), two pathways that promote cell
(FIG.2). Recently, many tools, including NOS inhibitors, survival and neuroprotection28,29. Finally, NO has been
NO donors and NO scavengers, have been discovered and shown to regulate cell signalling events by Snitrosylation
developed (TABLE1); their appropriate use allows researchers of pathway components, in which it binds covalently to
to specifically manipulate the NOSNO system. thiol groups of proteins and non-protein molecules30.
Through this reaction, NO exerts both neuroprotective
Isoform expression. The NOS family consists of three and neurotoxic effects (see below).
isoforms: neuronal NOS (nNOS, typeI); endothelial
NOS (eNOS, typeIII); and inducible NOS (iNOS, Nitric oxide and neurotransmission
typeII)1,12,13. Neuronal NOS and eNOS are constitutively The first evidence of a role for NO as a neurotrans
expressed and require the formation of Ca2+calmodulin mitter was reported by Garthwaite etal., who dem
complexes for their activation, whereas iNOS exerts its onstrated that stimulation of cerebellar NMDA
activity in a Ca2+-independent manner. All three NOS (Nmethyld-aspartate) receptors by glutamate
isoforms need co-factors, such as haem, tetrahydrobi caused the release of a diffusible molecule with strong
opterin, flavin adenine dinucleotide, flavin mononucle similarities to endothelial-derived relaxation factor
otide and reduced nicotinamide-adenine dinucleotide (EDRF)31. Shortly before this study was published,
phosphate, for catalytic activity1,12 (FIG.2). NO had been identified as the EDRF molecule32,33.
Subsequently, it was shown that NO acts as a neuro
Isoform localization. Several studies carried out in rodents transmitter in both the CNS and PNS by mechanisms
and primates have shown nNOS to be abundant in brain that are dependent on cyclic GMP34,35 (FIG.3).
areas such as the cerebral cortex, the ventral endopiriform Before discussing the direct effect of NO in neuro
nucleus, the claustrum, the olfactory bulb, the olfac transmission in the next section, it is interesting to note
tory nuclei, the nucleus accumbens, the striatum, the that this gaseous compound regulates the release of
amygdala, the hippocampus (in particular the CA1 classical neurotransmitters in many brain areas. In fact,
region and the dentate gyrus), the hypothalamus (the NO has been shown to indirectly stimulate the release of
supraoptic and paraventricular nuclei), the thalamus, the acetylcholine in the nucleus accumbens by stimulating
lateral dorsal and pedunculopontine tegmental nuclei,
the trapezoid body, the raphe magnus, the nucleus of sol H2N + NH2 H2N O
itary tract and the cerebellum1316. In the CNS, nNOS has Haem, BH4, Flavin
NH NH
also been found in astrocytes and cerebral blood vessels1.
In addition to this central localization, nNOS has been NADPH O2
+ NO
found in peripheral non-adrenergic, non-cholinergic NOS
neurons, which innervate the smooth muscle in the H3N+ COO
H3 N+ COO
adjacent glutamatergic neurons36. Basal NO concentra assigned to sleep control)45. Similarly, the microinjection
tions have been shown to reduce the release of GABA of the NO donor Snitroso-acetyl-penicillamine into
(aminobutyric acid) in a Ca2+- and Na+-dependent cat pedunculopontine tegmentum during wakefulness
manner37,38, whereas high levels of NO increase GABA increased both slow-wave sleep and rapid-eye move
release. NO donors stimulated the release of noradrena ment sleep46. Interestingly, 3bromo7-nitroindazole, a
line and glutamate in the hippocampus39 , whereas specific inhibitor of nNOS, was used to show that NO
haemoglobin, an endogenous NO scavenger, inhibited produced specifically by this NOS isoform regulates the
the release of these molecules. In the rat medial preoptic sleep process in rats47.
area, NO increased the release of both dopamine and
serotonin40 in an sGCcGMP-dependent way41. Nitric oxide and neurosecretion
In the telencephalon and the cerebellum, NO has an Neuronal NOS is localized in the hypothalamic
important role in the regulation of the synaptic plasticity supraoptic nucleus and the paraventricular nucleus,
that is involved in cognitive processes, such as memory. both of which are mainly involved in the neurosecre
Long-term potentiation (LTP) and long-term depres tory activity of this brain area48. In fact, the hypotha
sion (LTD) of synaptic transmission are well-established lamic paraventricular nucleus (parvicellular and
components of synaptic plasticity. Several lines of evi magnocellular portions) and the supraoptic nucleus
dence have shown that NO, produced presynaptically or (magnocellular portion) contain the cell bodies of
in interneurons, acts postsynaptically during cerebellar neurons that release corticotropin-releasing hormone
and striatal LTD, whereas the postsynaptic generation of (CRH), arginine vasopressin (AVP) and oxytocin49
this gaseous molecule and its action at presynaptic sites hormones that are implemented in stress and sleep
characterize NO as a retrograde diffusible messenger regulation, respectively.
in hippocampal and cortical LTP42. NOdependent LTP in
rat hippocampal and amygdala slices is inhibited by the The stress axis. CRH and AVP are the major neuropep
sGC inhibitor 1H[1,2,4]oxadiazolo[4,3a]quinoxalin1- tides that control the stress axis. When activated in
one (ODQ) (TABLE1), but enhanced by the sGC activator response to stress, neurons in the paraventricular nucleus
3(5-hydroxymethyl2-furyl)1-benzyl-indazole (YC1) release both CRH and AVP in the median eminence;
(TABLE1), demonstrating that the NOmediated modula these neuropeptides then travel to the anterior hypophysis
tion of synaptic plasticity is an sGCcGMP-dependent through the portal vessel system49. Once in the pituitary,
mechanism43,44. CRH and AVP activate corticotroph cells, which release
In the diencephalon, NO is a major regulator of the adrenocorticotropin-releasing hormone (ACTH) into
neurosecretory activity of the hypothalamus (see below the general circulation. ACTH, in turn, stimulates the
for further information). In the mesencephalon, NO is adrenal glands to release glucocorticoids50. AVP and oxy
involved in the regulation of many functions, including tocin can also be released from hypothalamic neurons in
the sleepwake cycle. larginine, the precursor of NO the posterior pituitary gland (the neurohypophysis), and
(FIG.2; TABLE1), caused an increase in slow-wave sleep from there directly into the systemic circulation, where
in rats when it was administered during the light phase AVP regulates water reabsorption by the kidney and oxy
into the pedunculopontine tegmentum (a brain area tocin is involved in the contraction of uterine smooth
Box 1 | Redox proteomics and the identification of nitrated proteins nutritional products or pharmacological compounds
represents an innovative approach to therapeutic
A redox proteomics approach was used to identify proteins that were modified intervention in diseases characterized by both oxida
specifically by nitration in the brains of patients with Alzheimers disease and mild tive and nitrosative stress, such as neurodegenerative
cognitive impairment10,11,116. This approach has provided new insight into potential
disorders19,77.
mechanisms of onset and progression of Alzheimers disease. Redox proteomics has the
potential to detect disease markers and identify potential targets for drug therapy in
neurodegenerative disorders. This technique78 involves the separation of brain proteins Curcumin. The polyphenolic molecule curcumin is
by two-dimensional (2D) SDSPAGE, followed by the detection, usually among a number of natural substances that show promise
immunochemically, of nitrated proteins (either from a 2D Western blot followed by spot in reducing nitrosative brain injury and delaying the onset
excision from a 2D gel, or from column eluates). Subsequent mass spectrometric of neurodegenerative disorders. It is a strong antioxidant
analysis of tryptic digests, combined with database searches, is used for protein that can inhibit lipid peroxidation, effectively intercept
identification78 (see figure). Almost uniformly, proteins that are identified as being and neutralize ROS and RNS98, and significantly increase
oxidatively modified by redox proteomics are dysfunctional117. haem oxygenase 1 expression in astrocytes and neurons99.
2D blot Dietary curcumin suppressed indicators of inflammation
and oxidative damage in the brains of a transgenic mouse
model of Alzheimers disease77,98.
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