Inactivation of nitric oxide by rat cerebellar slices

Hall, Catherine N.; Garthwaite, John

doi:10.1113/jphysiol.2006.118380

Cited by 41 publications

(80 citation statements)

References 58 publications

(86 reference statements)

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“…From the analysis, it was concluded that the above hypothesis was fully supported, subject to 2 main conditions: first, that the number of active nNOS neurons under low-leptin conditions is half or less than that present in the fully active state achieved after leptin treatment ( Figure 1C), and second, that NO was subject to a similar rate of inactivation to that found in the cerebellum (27) (see Supplemental Results). Accordingly, the model supports the idea that leptin treatment can switch the mode of operation of NO from being active only locally to being a "volume transmitter" capable of influencing cells located at a distance, irrespective of anatomical connectivity ( Figure 2C).…”

Section: Introductionmentioning

confidence: 83%

Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction

Bellefontaine¹,

Chachlaki²,

Parkash³

et al. 2014

J. Clin. Invest.

112

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The transition to puberty and adult fertility both require a minimum level of energy availability. The adipocyte-derived hormone leptin signals the long-term status of peripheral energy stores and serves as a key metabolic messenger to the neuroendocrine reproductive axis. Humans and mice lacking leptin or its receptor fail to complete puberty and are infertile. Restoration of leptin levels in these individuals promotes sexual maturation, which requires the pulsatile, coordinated delivery of gonadotropin-releasing hormone to the pituitary and the resulting surge of luteinizing hormone (LH); however, the neural circuits that control the leptin-mediated induction of the reproductive axis are not fully understood. Here, we found that leptin coordinated fertility by acting on neurons in the preoptic region of the hypothalamus and inducing the synthesis of the freely diffusible volume-based transmitter NO, through the activation of neuronal NO synthase (nNOS) in these neurons. The deletion of the gene encoding nNOS or its pharmacological inhibition in the preoptic region blunted the stimulatory action of exogenous leptin on LH secretion and prevented the restoration of fertility in leptin-deficient female mice by leptin treatment. Together, these data indicate that leptin plays a central role in regulating the hypothalamo-pituitary-gonadal axis in vivo through the activation of nNOS in neurons of the preoptic region.

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Section: Introductionmentioning

confidence: 83%

Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction

Bellefontaine¹,

Chachlaki²,

Parkash³

et al. 2014

J. Clin. Invest.

112

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“…NO can be broken down by several enzymes, including, in a cyanide-sensitive manner, CcO itself (Cooper et al 1997;Palacios-Callender et al 2007b). In cerebellar slices, however, an unknown cyanide-insensitive process predominates (Hall & Garthwaite, 2006) and exhibits Michaelis-Menten kinetics with a K m of ∼10 nM; for simplicity we assume that this process is independent of oxygen concentration. The different NOS isoforms have different kinetic characteristics.…”

Section: J Physiol 58615mentioning

confidence: 99%

“…The activity of each isoform depends on [O 2 ], and iNOS also shows feedback inhibition by NO which is competitive with O 2 (Santolini et al 2001). Ignoring any basal NO production, the profile of NO across a slice in which iNOS is active can therefore be generated by solving eqn (6), where D NO is 1.98 × 10 −3 cm 2 min −1 (Malinski et al 1993b) and K inact is 10 nM (Hall & Garthwaite, 2006). (6) where (7) gives K NO,iNOS = 1.19 μM.…”

Section: J Physiol 58615mentioning

confidence: 99%

“…(6) where (7) gives K NO,iNOS = 1.19 μM. The V max for NO inactivation (V inact ) was between 60 and 120 μM min −1 in acutely prepared slices (Hall & Garthwaite, 2006) but, as for O 2 consumption, there may well be differences between acutely prepared and cultured slices. The V max for NO production from iNOS (V iNOS ) in slices is also unknown.…”

Section: J Physiol 58615mentioning

confidence: 99%

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Assessing the physiological concentration and targets of nitric oxide in brain tissue

Hall

Attwell

2008

The Journal of Physiology

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Low nanomolar concentrations of nitric oxide activate guanylyl cyclase to produce cGMP, which has diverse physiological effects. Higher concentrations inhibit mitochondrial respiration at cytochrome c oxidase and this has been proposed to be important physiologically, increasing oxygen permeation into tissue (by reducing the oxygen use of cells near blood vessels), activating AMP kinase, and regulating the relationship between cerebral blood flow and oxygen use. It is unclear, however, whether nitric oxide can accumulate physiologically to concentrations at which inhibition of respiration occurs. In rat cerebellar slices, we activated nitric oxide production from each isoform of nitric oxide synthase. Only activation of inducible nitric oxide synthase, which is expressed pathologically, caused any significant inhibition of respiration. Modelling oxygen and nitric oxide concentrations predicted that, in vivo, physiological nitric oxide levels are too low to affect respiration. Even pathologically, the nitric oxide concentration may only rise to 2.5 nm, producing a 1.5% inhibition of respiration. Thus, under physiological conditions, nitric oxide signals do not inhibit respiration but are well-tuned to the dynamic range of guanylyl cyclase activation.

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“…Although the NO reductase activity of the enzyme is too slow to constitute a physiological mechanism for the removal of NO (22), there is strong evidence in favor of the oxidation of NO to NO 2 Ϫ both by the purified enzyme (23,24) and by cells (25). Nevertheless, the possibility that cytochrome c oxidase constitutes a significant metabolic route for NO remains controversial (26,27) and has been directly challenged (28).…”

mentioning

confidence: 99%

Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: A possible explanation for hypoxic vasodilation

Palacios-Callender

Hollis

Mitchison

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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One of the many routes proposed for the cellular inactivation of endogenous nitric oxide (NO) is by the cytochrome c oxidase of the mitochondrial respiratory chain. We have studied this possibility in human embryonic kidney cells engineered to generate controlled amounts of NO. We have used visible light spectroscopy to monitor continuously the redox state of cytochrome c oxidase in an oxygentight chamber, at the same time as which we measure cell respiration and the concentrations of oxygen and NO. Pharmacological manipulation of cytochrome c oxidase indicates that this enzyme, when it is in turnover and in its oxidized state, inactivates physiological amounts of NO, thus regulating its intra-and extracellular concentrations. This inactivation is prevented by blocking the enzyme with inhibitors, including NO. Furthermore, when cells generating low concentrations of NO respire toward hypoxia, the redox state of cytochrome c oxidase changes from oxidized to reduced, leading to a decrease in NO inactivation. The resultant increase in NO concentration could explain hypoxic vasodilation.hypoxia ͉ mitochondrial respiration ͉ nitric oxide inactivation ͉ nitric oxide synthase D espite much research on its metabolic fate, the way in which the concentration of nitric oxide (NO) is regulated in cells and tissues is at present unresolved. Many routes for its inactivation have been discussed, including interaction with superoxide ions (1), hemoglobin (2-4) or myoglobin (5), accelerated autoxidation favored by partition within cell membranes (6), and interactions with free radicals derived from eicosanoid lipoxygenase (7), cyclo-oxygenase (8), different peroxidases (9), or catalase (10). Interactions with a flavohemoglobin-like NO dioxygenase (11-13) or with an unknown protein (14), and simple partitioning within mitochondrial membranes (15), have also been suggested.Before the discovery of NO as a biological mediator (16) it had been shown that isolated cytochrome c oxidase, the terminal enzyme in the mitochondrial electron transport chain, catalyzes both the oxidation and reduction of NO (17). More recent evidence has suggested that cytochrome c oxidase may provide a metabolic route for NO, either by interaction of NO with the reduced enzyme, leading to the formation of N 2 O, (18,19) or by interaction of NO with the oxidized enzyme, forming nitrite (NO 2 Ϫ ; 20, 21). Although the NO reductase activity of the enzyme is too slow to constitute a physiological mechanism for the removal of NO (22), there is strong evidence in favor of the oxidation of NO to NO 2 Ϫ both by the purified enzyme (23, 24) and by cells (25). Nevertheless, the possibility that cytochrome c oxidase constitutes a significant metabolic route for NO remains controversial (26, 27) and has been directly challenged (28).Clarifying the route(s) of the cellular inactivation of NO will be important for a fuller understanding of its biological functions. We have therefore investigated the role of cytochrome c oxidase in the metabolic fate of NO by using our met...

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Inactivation of nitric oxide by rat cerebellar slices

Cited by 41 publications

References 58 publications

Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction

Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction

Assessing the physiological concentration and targets of nitric oxide in brain tissue

Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: A possible explanation for hypoxic vasodilation

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