ReviewNeuronal nitric oxide synthase: Structure, subcellular localization, regulation, and clinical implications
Introduction
Since awarding the Nobel Prize to R. Furchgott, L. Ignarro and F. Murad for their discovery of nitric oxide (NO) as a biological mediator, a rapidly expanding body of data have indicated the importance of nitric oxide in the physiology of the central nervous system [1], [2], [3]. There are three genetically different isoforms of nitric oxide synthase (NOS) which account for NO production. They include neuronal nitric oxide synthase (also known as nNOS, Type I, NOS-I and NOS-1) being the isoform found in neuronal tissues, inducible nitric oxide synthase (also known as iNOS, Type II, NOS-II and NOS-2) being the isoform which can be synthesized following induction by pro-inflammatory cytokines or endotoxin and endothelial nitric oxide synthase (also known as eNOS, Type III, NOS-III and NOS-3) being the isoform expressed in endothelial cells [4]. nNOS and eNOS are constitutively expressed and their activities are calcium-dependent, whereas the activity of iNOS is fully activated at basal intracellular calcium concentration, so its activity is calcium-independent [5]. Of the three NOS isoforms, nNOS constitutes the predominant source of NO in neurons and localizes to synaptic spines. Additionally, nNOS is also present in skeletal muscle, cardiac muscle and smooth muscle [6], [7], [8], [9], where NO controls blood flow and muscle contractility [10], [11], [12].
This review is intended to display the advances about nNOS over the last several years. It will address the structure, subcellular localization, regulation and concludes with a section discussing the role of nNOS in human physiologies and pathologies.
Section snippets
Structure
The neuronal NOS consists of 1434 amino acids with a predicted molecular weight of 160.8 kDa [13]. Monomer of nNOS is inactive, dimer is its active form and the dimerization requires tetrahydrobiopterin (BH4), heme and l-arginine binding [14]. nNOS monomer exhibits a bidomain structure containing an oxygenase domain (N-terminal) and a reductase domain (C-terminal) which can be separated by a calmodulin binding motif. The oxygenase domain which binds the substrate l-arginine contains a
Subcellular localization
nNOS is expressed in both immature and mature neurons [19], [20]. Besides, nNOS has also been found in rat astrocytes, the adventitia of rat brain blood vessels, rat cardiac myocytes, etc [21], [22]. Because NO can not be stored in the cells, it depends on new synthesis to exert its functional properties. Thus, to some extent, nNOS must be bond to the plasma membrane directly or be anchored to the plasma membrane by adapter proteins. Fractionation studies have demonstrated that brain nNOS
nNOS dimerization
Active nNOS is in a dimeric form, with an extensive interface being formed between the two oxygenase domains creating high-affinity binding sites for BH4 and l-arginine [28], [29]. nNOS monomer has two cysteine residues which can form a disulphide bridge or ligate a zinc ion between the monomers covalently linking the two oxygenase domains. Moreover, there is an ‘N-terminal hook’ domain which can also stabilize the dimer. Additionally, interactions across the dimmer between the reductase
Involvement of nNOS in physiologies and pathologies
Although nNOS-derived NO is a critical molecule in mediating synaptic plasticity and neuronal signaling, it changes from a physiological neuromodulator to a neurotoxic factor when excessive amount of NO is produced. So nNOS may play an important role in a wide range of physiological and pathological conditions.
Conclusions and perspectives
Collectively, nNOS is implicated in a wide range of functions and pathologies with pleiotropic effects. In view of its ubiquitous expression in the CNS, there are extensive and unique chances for nNOS to interact with other neuronal elements, thus exerting appropriate functional properties. Given increased nNOS activity and expression in many diseases, inhibiting nNOS might have putative therapeutic effects. Unfortunately, inhibiting nNOS directly may disturb physiological functions and produce
References (126)
- et al.
New aspects of the location of neuronal nitric oxide synthase in the skeletal muscle: a light and electron microscopic study
Nitric Oxide
(2005) - et al.
Neuronal-type NO synthase: transcript diversity and expressional regulation
Nitric Oxide
(1998) - et al.
Tetrahydrobiopterin inhibits monomerization and is consumed during catalysis in neuronal NO synthase
J. Biol. Chem.
(1999) - et al.
Intra-subunit and inter-subunit electron transfer in neuronal nitric-oxide synthase: effect of calmodulin on heterodimer catalysis
J. Biol. Chem.
(2001) - et al.
Important role of tetrahydrobiopterin in no complex formation and interdomain electron transfer in neuronal nitric-oxide synthase
Biochem. Biophys. Res. Commun.
(2001) - et al.
Role of bound zinc in dimer stabilization but not enzyme activity of neuronal nitric-oxide synthase
J. Biol. Chem.
(2000) - et al.
Electron transfer by neuronal nitric-oxide synthase is regulated by concerted interaction of calmodulin and two intrinsic regulatory elements
J. Biol. Chem.
(2006) - et al.
Differential vulnerability of immature murine neurons to oxygen-glucose deprivation
Exp. Neurol.
(2004) - et al.
The localization of neuronal nitric oxide synthase may influence its role in neuronal precursor proliferation and synaptic maintenance
Dev. Biol.
(2004) - et al.
Evidence of nuclear localization of neuronal nitric oxide synthase in cultured astrocytes of rats
Life Sci.
(2004)