Kinetics of nitric oxide‐cyclic GMP signalling in CNS cells and itspossible regulation by cyclic GMP

Wykes, Victoria; Bellamy, Tomas C.; Garthwaite, John

doi:10.1046/j.1471-4159.2002.01106.x

Cited by 41 publications

(42 citation statements)

References 46 publications

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“…The mechanism responsible for GC desensitization is unknown and is currently under investigation. Previously, circumstantial evidence indicated that it was related to the level of cGMP (13), and all of the data in the present study (with and without PDE inhibition) would be consistent with this proposal.…”

Section: Differential Potency Of No For Gc-coupled Receptors In Cellssupporting

confidence: 92%

“…GC and PDE Activities with Partial PDE Inhibition-Cells such as striatal neurons (13) and aortic smooth muscle (14) exposed to high NO concentrations produce a cGMP response having a triphasic shape resembling that found in platelets exposed to a low sildenafil concentration (1 M) (Fig. 3a).…”

Section: Expression Of Gc-coupled No Receptor Subunit Mrna Inmentioning

confidence: 91%

“…Although this rate seems high, platelets are not unique in this respect, because, after making corrections for the purity of the cells in question, an activity of this order exists in astrocytes from the cerebellum (10) and in a population of neurons from the striatum (13). The overriding difference between the three cell types analyzed so far is in PDE activity.…”

Section: Differential Potency Of No For Gc-coupled Receptors In Cellsmentioning

confidence: 99%

“…Desensitization of GC-coupled NO Receptors-GC desensitization had been described for cerebellar astrocytes, which naturally have only very low PDE activity (10), and for other cells when PDE activity was artificially reduced (10,13). The relevance of desensitization to cells that have higher PDE activity and/or to NO concentrations giving less than maximal stimulation was not known.…”

Section: Differential Potency Of No For Gc-coupled Receptors In Cellsmentioning

confidence: 99%

“…For example, in platelets (9, 10), mast cells (11), and a neuroblastoma cell line (12), the response to continued NO application is a transient increase in cGMP, whereas, in a population of glial cells from the cerebellum, cGMP rises hyperbolically with time to attain large plateau concentrations (10). An intermediate response is found in neurons in another part of the brain (13) and in aortic smooth muscle (14). The information encoded in the different cGMP profiles is unclear, but the temporal and amplitude characteristics presumably impact on the selection of downstream targets, which include protein kinases in the nanomolar concentration range (15) and ion channels in the micromolar range (16).…”

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confidence: 99%

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Kinetics of a Cellular Nitric Oxide/cGMP/Phosphodiesterase-5 Pathway

Amin

Bianco³

et al. 2004

Journal of Biological Chemistry

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103

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Rat platelets served as a model to evaluate quantitatively how guanylate cyclase (GC)-coupled nitric oxide (NO) receptors and phosphodiesterases (here phosphodiesterase-5) interact to transduce NO signals in cells. The platelets expressed mRNA only for the ␣ 1 and ␤ 1 GC-coupled receptor subunits. In intact platelets, the potency of NO for elevating cGMP (EC 50 ‫؍‬ 10 nM) was lower than in lysed platelets (EC 50 ‫؍‬ 1.7 nM). The limiting activities of GC and phosphodiesterase in intact platelets were both very high, being equivalent to about 100 M/s. With low phosphodiesterase activity (imposed by 100 M sildenafil), the cGMP response over time was hyperbolic in shape for a range of NO concentrations or GC activities due to GC desensitization. Without a phosphodiesterase inhibitor, NO generated only brief cGMP transients, peaking after 2-5 s but amounting maximally to about 150 M cGMP. The transients were caused partly by GC desensitization, which varied in rate (halftime up to 3 s) and extent (up to 80%) depending on the NO concentration, and partly by an enhancement of the phosphodiesterase catalytic activity with time, which was deduced to be up to 30-fold and to occur with a half-time of up to 5 s. The results were simulated by a quantitative model, which also explains the varied shapes of cGMP responses to NO found in other cells. Downstream phosphorylation in platelets was detectable within 2 s, and, with continuous exposure (1 min), this pathway could be engaged by subnanomolar NO concentrations (EC 50 ‫؍‬ 0.5 nM).Whereas the spatio-temporal dynamics of some of the primary steps of cellular signal transduction, such as synaptic transmission and changes in intracellular Ca 2ϩ , have become well understood in quantitative terms (1, 2), knowledge of downstream signaling cascades remains largely qualitative. Nevertheless, the kinetic properties of the second messenger cascades are likely to be similarly instrumental in determining how cells respond.A case in point is nitric oxide (NO) 1 signaling. NO acts as a diffusible chemical messenger throughout the body, where it subserves diverse functions, including smooth muscle relaxation, inhibition of platelet aggregation, and the induction of synaptic plasticity (3,4). NO elicits these and other physiological effects by binding to its guanylyl cyclase (GC)-coupled receptors, thereby evoking the accumulation of cGMP in target cells. The receptors are ␣␤-heterodimers, of which two main isoforms, ␣ 1 ␤ 1 and ␣ 2 ␤ 1 , exist at differing levels in different tissues (5). Studies on purified receptors (6) and intact cells (7) suggest that activation of GC occurs very rapidly, within a few ms or less of adding NO, and complete deactivation in cells (upon removal of NO) requires only about 500 ms (7). Furthermore, when studied in isolation, the receptors are highly sensitive NO detectors, with only about 1 nM being needed to evoke half-maximal GC activity (8). The shape of the resulting cGMP response in cells, however, varies greatly from one cell to another. For example,...

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Section: Differential Potency Of No For Gc-coupled Receptors In Cellssupporting

confidence: 92%

Section: Expression Of Gc-coupled No Receptor Subunit Mrna Inmentioning

confidence: 91%

Section: Differential Potency Of No For Gc-coupled Receptors In Cellsmentioning

confidence: 99%

Section: Differential Potency Of No For Gc-coupled Receptors In Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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Kinetics of a Cellular Nitric Oxide/cGMP/Phosphodiesterase-5 Pathway

Amin

Bianco³

et al. 2004

Journal of Biological Chemistry

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103

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Glial‐mediated neuroprotection: Evidence for the protective role of the NO‐cGMP pathway via neuron–glial communication in the peripheral nervous system

Thippeswamy

McKay

Morris

et al. 2004

Glia

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The NO-cGMP pathway has emerged as a neuroprotective signaling system involved in communication between neurons and glia. We have previously shown that axotomy or nerve growth factor (NGF)-deprivation of dorsal root ganglion (DRG) neurons leads to increased production of NO and at the same time an increase in cGMP production in their satellite glia cells. Blockade of NO or its receptor, the cGMP synthesizing enzyme soluble guanylate cyclase (sGC), results in apoptosis of neurons and glia. We now show that co-culture of neonatal DRG neurons with either Schwann cells pre-treated with an NO donor or a membrane-permeant cGMP analogue; or neurons maintained in the medium from Schwann cell cultures treated in the same way, prevents neuronal apoptosis. Both NO donor and cGMP treatment of Schwann cells results in synthesis of NGF and NT3. Furthermore, if the Schwann cells are previously infected with adenoviral vectors expressing a dominant negative sGC mutant transgene, treatment of these Schwann cells with an NO donor now fails to prevent neuronal apoptosis. Schwann cells treated in this way also fail to express neither cGMP nor neurotrophins. These findings suggest NO-sGC-cGMP-mediated NGF and NT3 synthesis by Schwann cells protect neurons.

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Nitric oxide signaling via cGMP‐stimulated phosphodiesterase in striatal neurons

Lin

Fretier

Jiang

et al. 2010

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Nitric oxide (NO) acts in the nervous system to activate guanylyl cyclase and increase cGMP. One target for cGMP appears to be the cGMP-stimulated phosphodiesterase (PDE2A), which is widely expressed in the brain and provides a molecular mechanism for NO to regulate cAMP levels. We have found that PDE2A is highly expressed in the medium spiny neurons of the striatum, which project to the pallidum and substantia nigra. These cells express dopamine-stimulated adenylyl cyclase, and we have found that increases in cAMP in these neurons, produced by activation of the D1-type dopamine receptor, are dramatically enhanced by the general phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and the PDE2A-selective inhibitor erythro-p-(2-hydroxyl-3-nonyl)adenine (EHNA). These results indicate that PDE2A plays a major role in regulating dopamine-stimulated cAMP production in striatal neurons. EHNA also enhances NO-induced increases in striatal cGMP. In addition, dopamine appears to act via another receptor, activated by the agonist SKF83959, to increase striatal cGMP in a NO-dependent manner. Together, these observations indicate that striatal NO producing interneurons can act via the PDE2A in the medium spiny neurons to regulate the cAMP response to dopamine stimulation.

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Kinetics of nitric oxide‐cyclic GMP signalling in CNS cells and itspossible regulation by cyclic GMP

Cited by 41 publications

References 46 publications

Kinetics of a Cellular Nitric Oxide/cGMP/Phosphodiesterase-5 Pathway

Kinetics of a Cellular Nitric Oxide/cGMP/Phosphodiesterase-5 Pathway

Glial‐mediated neuroprotection: Evidence for the protective role of the NO‐cGMP pathway via neuron–glial communication in the peripheral nervous system

Nitric oxide signaling via cGMP‐stimulated phosphodiesterase in striatal neurons

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