Nitric Oxide Synthase (NOS)-Interacting Protein Interacts with Neuronal NOS and Regulates Its Distribution and Activity

Dreyer, Jacqueline; Schleicher, Michael; Tappe, Anke; Schilling, Kirstin; Kuner, Thomas; Kusumawidijaja, Grace; Müller‐Esterl, Werner; Oess, Stefanie; Kuner, Rohini

doi:10.1523/jneurosci.2265-04.2004

Cited by 76 publications

(58 citation statements)

References 56 publications

(87 reference statements)

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“…On the other hand, these data may also suggest that elevations in [Ca 2ϩ ] i and nNOS dephosphorylation are required but not sufficient to induce nNOS activation and NO production and that other unknown PKA-dependent mechanisms are required for these processes. For instance, it has been demonstrated that NOSinteraction protein (NOSIP) interacts with and inhibits nNOS (Dreyer et al, 2004). The fact that NOSIP contains the consensus sequence for PKA supports the idea that PKA may [Ca 2ϩ ] i and NO production in hypothalamic neurons.…”

Section: Discussionmentioning

confidence: 88%

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

Krukoff²

2007

Mol Pharmacol

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Adrenomedullin (ADM) in the brain plays important roles in the maintenance of homeostasis. Although in vivo evidence has suggested that nitric oxide (NO) mediates ADM's effects in the brain, mechanisms for ADM stimulation of NO production in neurons have not been identified. In the present study, primary hypothalamic neurons were used to characterize ADM-induced NO production and to study the underlying mechanisms. Using Calcium Orange/4-amino-5-methylamino-2Ј,7Ј-difluorofluorescein fluorescence live cell imaging, we found that ADM (1 or 10 nM, 5 min) significantly elevated [Ca 2ϩ ] i and NO production in a concentration-dependent manner. Ca 2ϩ and NO responses induced by 10 nM ADM were abolished by pretreatment with 50 M 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid-acetoxymethyl ester (BAPTA-AM), an intracellular Ca 2ϩ chelator, or protein kinase A (PKA) inhibitors 5 M N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) and 50 M Rp-cAMP. Furthermore, the ADM-induced NO production was significantly attenuated by a protein phosphatase 1/2A inhibitor, okadaic acid (OA; 0.1 M), or calcineurin inhibitors, tacrolimus (FK506) (1 M) and cyclosporin A (CsA; 0.1 M). Using Western blotting, we found that ADM significantly decreased phosphorylation of neuronal nitric-oxide synthase (nNOS) at serine 847. This dephosphorylation was inhibited by 0.1 M OA, 1 M FK506, 0.1 M CsA, or 5 M H-89, and attenuated by 50 M BAPTA-AM. These results suggest that, in hypothalamic neurons, ADM elevates [Ca 2ϩ ] i via PKA-associated mechanisms. The PKA/Ca 2ϩ cascade leads to protein phosphatase (PP) 1/PP2A-and calcineurin-mediated dephosphorylation of nNOS. We hypothesize that the Ca 2ϩ increase and nNOS dephosphorylation contribute to activation of nNOS and production of NO in hypothalamic neurons.

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Section: Discussionmentioning

confidence: 88%

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

Krukoff²

2007

Mol Pharmacol

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“…Another protein that inhibits NO productions is nitric oxide synthase interacting protein (NOSIP) [29]. NOSIP and nNOS co-localize in different areas of the central and peripheral nervous systems.…”

Section: Nnos Inhibitorsmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase

Arami¹,

Jameie²,

AkbarMoosavi³

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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Nitric oxide synthase (NOS), a flavo-hemoprotein, regulates nitric oxide (NO) synthesis that has dual biological activities: as an important signalling molecule in vasodilatation and neurotransmission at low concentrations and at higher concentrations as a defensive cytotoxin. In central and peripheral nervous system, neuronal NOS (nNOS) produces NO that has been implicated in modulating physiological functions such as synaptic plasticity, learning, memory and neurogenesis as well as some pathological conditions in which overproduction of NO may lead to the generation of highly reactive species, such as peroxynitrite and stable nitrosothiols, which may cause irreversible cell damage in excitotoxicity, ischaemia, Parkinson, Alzheimer's disease (AD) and depression. NOSderived NO also involves in regulation of blood pressure, smooth muscle relaxation and gut peristalsis via peripheral nitrergic nerves.

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“…Of the three NO synthese isoforms, nNOS is mainly localized in the central nervous system, postsynaptic density (PSD), and muscular sarcolemma (muscle fiber myelin) and participates in neural transmission [39][40][41]. iNOS is usually not expressed, but is induced in vascular smooth muscle cells and macrophages via cytokine stimulation during sepsis or ischemia with or without reperfusion, and produces large quantities of NO [42].…”

Section: Discussionmentioning

confidence: 99%

Biphasic Action of Inducible Nitric Oxide Synthase in a Hindlimb Ischemia Model

Kimura

Goto

Yagi

et al. 2006

J. Clin. Biochem. Nutr.

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Summary We investigated the influence of inducible nitric oxide synthase (iNOS) on acute ischemic injury and chronic angiogenesis. In a hindlimb ischemia model, NO produced by endothelial NO synthase (eNOS) reduces ischemic injury and promotes angiogenesis. However, the effect of the large amounts of NO generated by induced iNOS is unclear. Experimental groups of mice were as follows: (1) wild-type group (Wild), (2) iNOS-knockout group (iNOS-KO), and (3) aminoguanidine-treated wild-type group (Wild + AG), which received aminoguanidine from day 0 to day 3 after ischemia. Acute ischemic injury was evaluated by measuring the plasma CK value and ischemic score. Chronic angiogenesis was evaluated by microangiography and with a non-contact type Doppler blood flowmeter on day 3. Compared with the Wild group (251 ± 34.7 IU/l), the CK value was significantly elevated in the iNOS-KO (497 ± 126.7 IU/l) and Wild + AG (587.2 ± 128.7 IU/l) groups. The ischemic score was significantly increased in the iNOS-KO (92%) and Wild ± AG (66.6%) groups compared with the Wild group (23%). Blood flow was significantly increased in the iNOS-KO group (58.7 ± 15.3%) compared with the Wild (38.1 ± 15.9%) and Wild ± AG (43.5 ± 9.8%) groups in the chronic stage. Microangiography revealed a significantly increased number of blood vessels in the iNOS-KO (0.29 ± 0.02) group compared with the Wild (0.12 ± 0.01) and Wild + AG (0.15 ± 0.02) groups. Our findings indicate that NO generated by iNOS has a biphasic action, reducing acute ischemic injury and inhibiting angiogenesis in the chronic stage.

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Nitric Oxide Synthase (NOS)-Interacting Protein Interacts with Neuronal NOS and Regulates Its Distribution and Activity

Cited by 76 publications

References 56 publications

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

Neuronal Nitric Oxide Synthase

Biphasic Action of Inducible Nitric Oxide Synthase in a Hindlimb Ischemia Model

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