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(Circulation Research. 2003;93:96.)
© 2003 American Heart Association, Inc.

Review

Regulation of Nitric Oxide-Sensitive Guanylyl Cyclase

Andreas Friebe, Doris Koesling

From Abteilung für Pharmakologie, Medizinische Fakultät, Ruhr-Universität Bochum, Bochum, Germany.

Correspondence to Doris Koesling, Abteilung für Pharmakologie, Medizinische Fakultät, Ruhr-Universität Bochum, Universitätsstr. 150, 44780 Bochum, Germany. E-mail doris.koesling{at}ruhr-uni-bochum.de

Rudi Busse Editor This Review is part of a thematic series on Cyclic GMP-Generating Enzymes and Cyclic GMP-Dependent Signaling, which includes the following articles:

Regulation of Nitric Oxide-Sensitive Guanylyl Cyclase
   Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function
   Structure, Regulation, and Function of Membrane Guanylyl Cyclase Receptors, With a Focus on GC-A
   Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System: Insights From Genetically Modified Mice
   Regulation of Gene Expression by Cyclic GMP
   Explaining the Phenomenon of Nitrate Tolerance

	Abstract

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
In this review, we outline the current knowledge on the regulation of nitric oxide (NO)-sensitive guanylyl cyclase (GC). Besides NO, the physiological activator that binds to the prosthetic heme group of the enzyme, two novel classes of GC activators have been identified that may have broad pharmacological implications. YC-1 and YC-1-like substances act as NO sensitizers, whereas the substance BAY 58-2667 stimulates NO-sensitive GC NO-independently and preferentially activates the heme-free form of the enzyme. Sensitization and desensitization of NO/cGMP signaling have been reported to occur on the level of NO-sensitive GC; in the present study, an alternative mechanism is introduced explaining the adaptation of the NO-induced cGMP response by a long-term activation of the cGMP-degrading phosphodiesterase 5 (PDE5). Finally, regulation of GC expression and a possible modulation of GC activity by other factors are discussed.

Key Words: cyclic GMP • guanylyl cyclase • nitric oxide • phosphodiesterase • sensitization/desensitization

	Introduction

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
Nitric oxide (NO)-sensitive guanylyl cyclase (NO-sensitive GC) is generally accepted as the most important receptor for the signaling molecule NO. This enzyme is also known as soluble or cytosolic GC, a designation chosen to distinguish the enzyme from its membrane-bound counterpart. Because recently one of the isoforms of the "soluble" GC has been found to associate with the cell membrane, we will use the term "NO-sensitive" GC throughout this review.

NO-sensitive GC is a heterodimer consisting of two different subunits termed and ß. The enzyme was shown to contain heme as a prosthetic group.¹ Stimulation of the enzyme by its physiological activator NO leads to a tremendous, up to 200-fold increase in catalytic rate, ie, the conversion of GTP to cyclic guanosine monophosphate (cGMP). NO-sensitive GC, similar to other nucleotide-converting enzymes, requires Mg²⁺ as cofactor for catalysis. The NO-induced cGMP signal is conveyed intracellularly by the activation of several effector molecules: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cGMP-gated ion channels. Most of the cGMP effects have been shown to be mediated by the cGMP-dependent kinase. Although the occurrence of cGMP-gated channels has been demonstrated outside sensory cells, their functional role remains to be established. The NO/cGMP signaling cascade (Figure 1) is of importance in the cardiovascular and nervous systems, where it controls smooth muscle relaxation,^2,3 modulation of synaptic transmission,^4–6 and inhibition of platelet aggregation.^7,8

View larger version (30K): [in this window] [in a new window]   Figure 1. NO/cGMP signaling cascade. NO endogenously produced by NO synthases or released from exogenously applied NO donors activates NO-sensitive GC and leads to increased synthesis of cGMP. This intracellular messenger in turn modulates the activity of cGMP-dependent kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesterases. These effectors are involved in the regulation of several physiological functions in the cardiovascular and nervous systems. YC-1 and BAY 58-2667 represent new classes of activators of NO-sensitive GC.

Although cGMP-forming activity was first described in 1969,^9–13 it took until the mid-1970s to find out that there are two different types of GC,¹⁴ which were subsequently found to differ not only in their cellular localization (cytosolic versus membrane-bound) but also in their structure and regulation (see review¹⁵). The membrane-bound, peptide-activated GCs are structurally related to the cytosolic enzymes but are not stimulated by NO. These GCs belong to the group of receptor-linked enzymes containing one membrane-spanning region. For detailed review of this GC family, see the article "Guanylyl Cyclase Receptors" in this series.

	Isoforms and Structure of NO-Sensitive GC

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
Purification of NO-sensitive GC from tissues of various organisms such as rat and bovine lung and brain was achieved by several groups. Subsequently, the ₁ and ß₁ subunits with molecular masses of 73 and 70 kDa, respectively, were cloned and sequenced.^16–19 The so-called ₃ and ß₃ subunits of NO-sensitive GC²⁰ represent human variants of the ₁ and ß₁ subunits rather than different isoforms, and changes in the reading frame account for the differences in amino acid sequences.²¹

Homology screening yielded another subunit of NO-sensitive GC, ₂.²² The occurrence of the ₂ subunit was demonstrated on the protein level in human placenta, and the ß₁ subunit was identified as the dimerizing partner.²³ Despite little sequence homology between the two subunits in the N-terminal domains, no differences in catalytic activity, NO stimulation, or substrate affinity could be detected between the ₁ß₁ and the ₂ß₁ heterodimers. Recent data suggest that the C-terminal peptide of the ₂ subunit defines the particular property of this subunit: the ability to interact with PDZ domains. Through the interaction with the PDZ domain-containing protein PSD-95, the ₂ß₁ heterodimer was shown to be localized to synaptic membranes.²⁴ In accordance with a putative role in synaptic transmission, the highest expression of the ₂ subunit was found in brain. Furthermore, the ß₁ subunit was detected at the presynaptic membrane of CA1 pyramidal cells, with nNOS being expressed in the postsynaptic side underlining the potential role of NO/cGMP signaling in the regulation of synaptic plasticity.²⁵ Nevertheless, ₂ is not the only subunit in brain; ₁ occurred in similar amounts. In all other tissues tested, the ₁ subunit was the major occurring subunit.²⁶ It appears that the expression of ₁ subunit correlates with the degree of vascularization.

Like ₂, the ß₂ subunit was identified by homology screening.²⁷ However, existence of the ß₂ subunit on the protein level appears unlikely; in the human gene, a base deletion has been described that results in a shift of the reading frame excluding functional expression of the protein.²⁸ Quantitative PCR analysis of mouse tissue revealed virtually no mRNA for the ß₂ subunit.²⁶ In addition, no convincing evidence of a functionally active ß₂-containing dimer has been presented so far.

NO-sensitive GC is catalytically active only as a heterodimer.^29,30 Homodimeric enzymes (₁₁and ß₁ß₁) have been purified from Sf9 cells; however, no enzymatic activity of these homodimers has been detected.³¹

A comparison of the primary structure shows that the subunits can be divided into three domains: a C-terminal catalytic domain, a central part, and an N-terminal region. The catalytic C-terminal domains of each subunit of NO-sensitive GC display the highest degree of homology.³² These domains are also very similar to the respective regions in the peptide-activated, membrane-bound guanylyl cyclases and in the adenylyl cyclases (AC). The catalytic domains of AC and NO-sensitive GC are structurally closely related as shown by the functional expression of AC/GC heterodimers³³ and the conversion of nucleotide specificity by the mutation of only three amino acids.³⁴ In the crystal structure obtained for these AC domains,^35,36 the binding site for the activator forskolin has been identified. The analogous region in NO-sensitive GC may be of special interest with regard to the possible binding site of the activator YC-1 (see later section).

The central regions preceding the catalytic domains show considerable homology to the membrane-bound enzymes.³⁷ In analogy, these regions are probably involved in the dimerization of the subunits, although detailed investigation is still missing.

The N-terminal regions of the subunits of NO-sensitive GC comprise the heme-binding domain. The prosthetic heme group mediates the NO-induced stimulation subsequent to binding NO. A histidine residue (His-105) within this region of the ß₁ subunit was shown to bind to the heme iron, thereby acting as the proximal ligand. Deletion of His-105 has been shown to abrogate NO activation of the enzyme.³⁸

	Prosthetic Heme Group

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
NO-sensitive GC is a hemoprotein and presence of the prosthetic heme group is mandatory for the activation of the enzyme by NO.^39,40 Removal of the heme group abolishes NO-induced activation, which can be restored after reconstitution of NO-sensitive GC with heme.^41,42 The heme stoichiometry has been agreed to be one mole per mole GC heterodimer. The absorbance maximum at 430 nm is indicative for a five-coordinated ferrous heme with a histidine as the axial ligand.⁴³ In contrast to other hemoproteins such as hemoglobin or myoglobin, the heme of NO-sensitive GC does not bind oxygen.^1,44

Both, the and ß subunits are required for proper binding and orientation of the heme group. Sequential truncation showed that the subunits contribute unequally to heme binding with the ß₁ subunit playing a more important role⁴⁵; in addition, homodimers of the N-terminal part of the ß₁ subunit (the first 385 amino acid) expressed in bacteria were shown to bind heme in a manner similar to the wild-type enzyme.⁴⁶

The His-105 of the ß₁ subunit was identified as the heme coordinating residue.^38,47 Mutation of this histidine led to the generation of an NO-insensitive, heme-depleted enzyme with intact basal activity. In addition, two conserved cysteines adjacent to the His-105 on the ß₁ subunit appear to play a role in the formation of the proper heme pocket. Mutation of these residues led to loss of enzyme-bound heme and NO responsiveness, which could be regained after heme reconstitution.⁴⁸

	Activation of NO-Sensitive GC by NO

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
Already in the 1970s, NO-releasing compounds were found to be potent activators of NO-sensitive GC.^49,50 Similarly, nitrovasodilators like glyceroltrinitrate or isosorbid dinitrate therapeutically used for the treatment of coronary heart disease act by stimulation of the enzyme. These nitrates do not release NO spontaneously; instead, they have to undergo bioactivation that either yields NO or nitrosothiols.

Despite the stimulatory effect of these NO-containing compounds, the physiological significance of NO-induced activation of the enzyme did not become apparent until the identification of endothelium-derived relaxing factor (EDRF) as NO.^51,52 Formation of EDRF had been shown to occur in endothelial cells in response to vasodilatory agonists such as acetylcholine, histamine, or bradykinin, leading to vasodilation via the activation of NO-sensitive GC in smooth muscle cells.⁵³ After the discovery of NO in the vascular system, NO formation was reported to occur throughout the body.⁵⁴ The enzymes responsible for the synthesis of NO were identified and termed NO synthases of which three isoforms are known to date. The inducible isoform produces relatively high NO concentrations and thereby exhibits direct toxic effects. The enzyme is mainly expressed in macrophages and plays a role in the nonspecific immune response. The neuronal and endothelial NO synthases are constitutively expressed enzymes that are regulated by the intracellular calcium concentration. The endothelial NO synthase is also activated by Akt/PKB-dependent phosphorylation triggered by shear forces exerted on the endothelial cells.⁵⁵ Both isoforms produce relatively low NO concentrations (1 to 100 nmol/L). At these low concentrations, NO functions as a signaling molecule, and most of its effects are mediated via the activation of NO-sensitive GC.

In fact, an EC₅₀ value for NO-sensitive GC as low as 2 nmol/L NO has been determined in cerebellar cell suspensions using a technique to deliver constant concentrations.⁵⁶ Thus, activation of NO-sensitive GC in intact cells can be achieved at concentrations that are below those potentially inhibitory for other cellular targets such as mitochondrial cytochromes.⁵⁶ NO donors, commonly used in in vitro and in vivo studies, differ in parameters like NO release or thiol requirement. For this reason, EC₅₀ values reported for these substances vary considerably depending on the donor and the assay system used. Whereas NO donors such as GSNO or SNP have to be used at micromolar concentrations for half-maximal activation, the frequently used compound DEA-NO, which releases NO spontaneously, shows an EC₅₀ value of approximately 300 nmol/L.^24,57

	Mechanism of Activation

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
Among the three redox forms of NO (NO^-, NO, NO⁺), only the uncharged NO radical (NO^·) has been shown to significantly activate NO-sensitive GC.⁵⁸ Activation of the enzyme by NO involves the binding to the enzyme’s prosthetic heme group, which leads to the up to 200-fold activation of the enzyme.^43,59

The heme group of NO-sensitive GC exhibits an absorbance maximum at 431 nm, which is indicative of a five-coordinated ferrous heme with a histidine as the axial ligand at the fifth coordinating position.⁴³ Several models exist to explain the activation of NO-sensitive GC, the simplest is thought to occur in two steps: binding of NO to the sixth coordination position of the heme results in a six-coordinated NO-Fe²⁺-His-complex. The subsequent breakage of the histidine-to-iron bond leads to the formation of a five-coordinated nitrosyl-heme complex with an absorbance maximum at 398 nm. The opening of the histidine-to-iron bond is considered to initiate a conformational change resulting in the activation of the enzyme. In support of this simple model, protoporphyrin IX activates NO-sensitive GC independently of NO.⁶⁰ Protoporphyrin IX, the iron-free precursor of heme, structurally resembles the NO-heme complex in which the iron is moved out of the plane of the porphyrin ring. Thus, in both structures, the axial histidine is unbound. However, the release of the histidine-iron bond appears not to be sufficient for the activation of NO-sensitive GC as a mutant lacking the proximal histidine did not show an increased catalytic rate. Therefore, the proximal histidine not only coordinates the heme group but also mediates the stimulatory action.

Recently, a more complex model of NO activation has been introduced. By using stopped-flow spectroscopy, Zhao et al⁶¹ investigated the subsecond kinetics of NO activation of NO-sensitive GC and provided data that the transition from the six-coordinate to the five-coordinate complex depended on the NO concentration present. This results in a model where NO not only activates the enzyme by binding to the heme but also regulates the velocity of activation via binding to a second non-heme binding site. However, Bellamy et al,⁶² reinterpreted the data by Zhao et al in favor of the simple two-state model and claimed the postulated additional NO site as unnecessary. These two models are currently disputed between the two groups.^62,63

	Deactivation of NO-Sensitive GC

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
In an early study, Palmer et al⁵¹ showed that NO/EDRF-induced relaxation of aortic rings could be reinduced already 1 to 2 minutes after the first stimulus, indicating fast deactivation of NO-sensitive GC in the biological system. Further studies on NO dissociation and deactivation have been performed with purified enzyme, cytosolic fractions, and intact cells.

NO dissociation measured spectrophotometrically resulted in a half-life of the NO-GC complex of approximately 2 minutes, which was accelerated to a half-life of 5 seconds by the addition of the substrate MgGTP.^64,65 This accelerating effect of GTP is corroborated by a study using resonance Raman spectroscopy, which suggested binding of GTP in the proximity of bound NO, thereby possibly regulating NO binding.⁶⁶ A half-life of approximately 3 minutes but no increase in the NO dissociation rate on the addition of MgGTP was shown in a different spectrophotometric study.⁶⁷

The half-life of approximately 5 seconds for the NO-GC complex was confirmed monitoring deactivation, ie, the decline in cGMP forming activity of the purified enzyme⁶⁸ or in cytosolic preparations of retina.⁶⁹ Measurements in intact cerebellar cells showed an even 10-fold faster deactivation with a half-life of 0.2 seconds.⁷⁰ In conclusion, deactivation of NO-sensitive GC was shown to be in the range required for rapid signaling in various systems. Additional research is necessary to unravel the special feature of the heme group of NO-sensitive GC permitting such fast NO dissociation.

	Inhibitors

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
Several substances have been found to inhibit NO-sensitive GC. The quinoxalin derivative 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ; Figure 2) was shown to be a potent and selective inhibitor of NO-sensitive GC in brain slices.⁷¹ ODQ does not lead to the inhibition of the membrane-bound guanylyl or adenylyl cyclases and interferes with the stimulation of NO synthase and other heme proteins only at high concentrations.⁷² Therefore, ODQ represents an important tool to discriminate cGMP-dependent and cGMP-independent effects of NO. Inhibition of NO-sensitive GC by ODQ has been demonstrated in a variety of other cells and tissues.^71,73–75 Studies with purified NO-sensitive GC revealed that ODQ binds in an NO-competitive manner and leads to an apparently irreversible inhibition of the stimulated enzyme leaving basal activity unchanged. Spectral analysis suggests oxidation of the heme iron as underlying mechanism of the inhibitory effect.^76,77 The notion that the heme iron is the target of ODQ is confirmed by the finding that ODQ is not able to inhibit the stimulation of NO-sensitive GC induced by the iron-free protoporphyrin IX.⁷⁸ A derivative of ODQ, NS 2028 (oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one), has been published to have properties similar to those of ODQ.⁷⁹

View larger version (18K): [in this window] [in a new window]   Figure 2. Pharmacological compounds acting on NO-sensitive GC. YC-1 and BAY 58-2667 are novel activators of NO-sensitive GC that increase cGMP production independent of NO. YC-1 potentiates the stimulatory action of NO and thus serves as "NO sensitizer"; BAY 58-2667 preferentially activates the heme-depleted form of the enzyme. ODQ, in contrast, inhibits NO-sensitive GC by oxidizing the heme iron leaving basal activity intact.

Other inhibitors such as methylene blue and LY-83583 show less specificity than ODQ and, eg, inhibit the olfactory cyclic nucleotide-gated ion channel⁸⁰ or interfere with NO formation and NO release from NO synthases⁸¹; therefore, ODQ should be preferred as specific GC inhibitor.

	Novel Activation Mechanisms of NO-Sensitive GC

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
Besides the well-established NO/heme-mediated stimulation, two novel mechanisms of activation have been identified for NO-sensitive GC, indicating considerable therapeutic potential (Table). First, the activator YC-1 (see Figure 2) was shown to act as an "NO sensitizer," greatly enhancing the sensitivity of GC toward NO.^82,83 Derivatives of YC-1 and other novel substances have been identified^84–87 (for structure-function relationship, see Selwood et al⁸⁸). By increasing the NO responsiveness under pathological conditions characterized by reduced NO release, these NO sensitizers may become important drugs in the treatment of various cardiovascular diseases. Moreover, with the substance BAY 58-2667 (see Figure 2), another mode of GC activation has been described recently. This substance was reported as an NO-independent activator whose effect was even more pronounced on the heme-free enzyme.⁸⁹ Both YC-1 and BAY 58-2667 have been shown to exert beneficial effects in the cardiovascular system based on their antiplatelet and vasodilatory activity.⁸⁹ The effects of both classes of activators on NO-sensitive GC will be discussed in the following section.

View this table: [in this window] [in a new window]   Table 1. Maximal Stimulation of NO-Sensitive GC by Different Classes of Activators

YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole)⁹⁰ was the first compound of this series to be identified. Originally, YC-1 had been published as an activator of NO-sensitive GC in rabbit and human platelets leading to an increase in the intracellular cGMP concentration.^91,92 YC-1 causes a 10-fold activation of purified NO-sensitive GC independent of NO.^82,93 Despite this NO independence, YC-1 failed to stimulate the heme-free enzyme, showing that the effect of YC-1 required the presence of the prosthetic heme group. Most interestingly, YC-1 sensitized NO-sensitive GC toward NO as YC-1 shifted the EC₅₀ for NO to the left by one order of magnitude.^82,93 Mechanistically, YC-1 was shown to slow down deactivation of NO-stimulated GC, which is sufficient to explain the sensitizing effect of YC-1.^68,83 Rather unexpectedly, YC-1 also turned CO into an effective activator, despite the fact that by itself, CO is hardly able to activate the purified enzyme.^82,94

By spectral analysis and enzyme studies, YC-1 was shown to bind to a site different from the heme group, suggesting a so far unknown allosteric site on the enzyme.⁸³ Controversial reports exist on the localization of this allosteric site. In order to identify this site, Stasch et al⁹⁵ used a novel high-affinity YC-1 analogue, BAY 41-2272, as photoaffinity label. An N-terminal region of the ₁ subunit (amino acids 236 to 290) was identified to comprise the YC-1 binding site. However, this region is not conserved in the ₂ subunit albeit the ₂-containing heterodimer exhibits virtually identical sensitivity toward YC-1.²³ In theory, the structural similarity between AC and GC in combination with the sensitizing effect of the respective activators forskolin and YC-1 suggest the C-terminal catalytic region as the YC-1 binding site (see previous section); this notion is supported by different mutations within this region of GC either mimicking or abolishing the effects of YC-1.^68,96 Nevertheless, definitive conclusions about the allosteric site involved in NO sensitization of the enzyme await protein crystallography.

The effects of YC-1 on NO/cGMP signaling have been investigated in a variety of cells and tissues. In vascular smooth muscle cells, YC-1 was reported to increase cGMP levels and to induce a concentration-dependent relaxation of endothelium-denuded rat aortic rings.^93,97,98 Other tissues in which YC-1 induced cGMP elevations include guinea pig trachea,⁹⁹ guinea pig colon,¹⁰⁰ corpus cavernosum,¹⁰¹ and pig urethra.¹⁰² In endothelial cells, the YC-1 induced cGMP increases were most pronounced as in these cells YC-1 did not only stimulate NO-sensitive GC directly but also potentiated the stimulatory effect of the endogenously synthesized NO.¹⁰³

In platelets, YC-1 was shown to inhibit adhesion and aggregation.^92,104,105 In these cells, YC-1 led to a drastic, over 1000-fold increase in cGMP in the presence of NO. Closer analysis revealed that YC-1 inhibited various PDEs.^98,105 Due to the high catalytic rate of PDEs, some of the YC-1 effects observed in intact cells may be caused by the inhibition of PDEs rather than solely by the stimulation of NO-sensitive GC.

A second novel mechanism of activation has been shown to occur using the substance BAY 58-2667.⁸⁹ This compound, an amino dicarboxylic acid, alone led to a moderate activation of NO-sensitive GC; this stimulation was additive to that of NO, which is in contrast to the potentiation seen with YC-1. Surprisingly, BAY 58-2667 stimulated the heme-oxidized or heme-depleted purified enzyme almost 200-fold. This indicates that BAY 58-2667 may be able to substitute for the heme group or stabilize the heme-free conformation; the occurrence of the heme-free form of NO sensitive GC under physiological conditions remains to be elucidated. Photoaffinity labeling and binding studies suggest binding of the compound to both subunits of NO-sensitive GC.

	Sensitization/Desensitization Within NO/cGMP Signaling

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
In the cardiovascular system, NO/cGMP signaling is important in the regulation of vascular tone and primary hemostasis. As NO-sensitive GC occurs mainly in smooth muscle cells and platelets, many studies have been performed in either cell type, and NO sensitivity has been shown to vary. This section concentrates on the modulation of NO-sensitive GC and beyond in the cGMP signaling cascade; the broader phenomenon of NO tolerance, which also includes NO bioavailability, is being covered in another article of this series.

Sensitization/desensitization describe an alteration of the NO/cGMP response toward a given NO challenge. This process may be caused by a change in enzyme reactivity, eg, by posttranslational modification, or an alteration of the amount of the enzyme present, the latter being discussed in the next section. Sensitization/desensitization of the cGMP response has been mostly attributed to a changed responsiveness of NO-sensitive GC. However, the impact of cGMP degradation has not been examined in most cases.

First reports on an increased sensitivity of the NO-induced cGMP response have been performed on isolated blood vessels that were either endothelium-denuded or in which endothelial NO production was impaired by inhibitor treatment.^106–108 In all these studies, removal of NO led to an increase in the potency of vasodilators used for relaxation. These in vitro data were corroborated in in vivo experiments by Moncada et al¹⁰⁹ who found an enhanced antihypertensive response to glyceryltrinitrate in rats treated with inhibitors of eNOS. This "supersensitive" state did not require long-term treatment but was also detected in vessels treated with L-NAME for only 15 minutes. More recent reports show similar results in mice lacking the endothelial NO synthase.¹¹⁰ Thus, reduction of the NO concentration in vitro or in vivo leads to an increase in sensitivity of the signaling pathway.

Vice versa, decreased sensitivity of the NO/cGMP system has been demonstrated under various conditions after treatment with NO-releasing agents.^111–113 Transgenic mice overexpressing eNOS showed a decreased response toward endothelium-dependent and -independent vasorelaxation, which was attributed to a decreased activity of NO-sensitive GC.¹¹⁴ In a recent report, Bellamy et al¹¹⁵ showed a rapid NO-induced desensitization of NO-sensitive GC within seconds.

Despite these reports, factors responsible for sensitization/desensitization of NO-sensitive GC have not been identified so far (for phosphorylation, see next section). Although regulation of NO-sensitive GC by thiol-modifying or redox-active substances like superoxide has been postulated for more than 30 years, the functional consequences have not been unequivocally demonstrated on the purified enzyme, and the underlying molecular modifications are unknown. Theoretically, NO sensitivity of GC could be controlled by the heme content of the enzyme. However, the heme/protein ratio of 1 mole per mole obtained in several purification procedures from different tissues argues against a varying heme content. Besides, mice with limited heme synthesis were shown to contain a normally functioning NO-sensitive GC.¹¹⁶ Thus, a molecular mechanism for sensitization/desensitization of NO-sensitive GC is still lacking.

In most of these cases, sensitization/desensitization of the cGMP response was assessed by measuring intracellular cGMP levels not taking into account the downstream cGMP-degrading activity of phosphodiesterases (PDE). Recent results on cGMP-induced stimulation of PDE5 provide another possibility to explain the sensitization/desensitization within NO/cGMP signaling. In platelets, the NO-induced cGMP response was fast (less than a minute) and controlled by PDE5 activity.¹¹⁷ Desensitization did not occur on the level of NO-sensitive GC, which remained fully active but was attributed to an increased activity of PDE5. PDE5 is directly activated by cGMP binding to one of the enzyme’s regulatory GAF domains (GAF-A).¹¹⁸ Surprisingly, PDE5 activation was very sustained and still observed 1 hour after the removal of NO.¹¹⁹ PDE5 activation was paralleled by phosphorylation by the cGMP-dependent protein kinase I, which increases the cGMP affinity of the GAF-A domain.¹²⁰ The exact mechanism of cGMP-induced activation of PDE5 is outlined in more detail in another article of this series. In sum, there is evidence for a new, so far unknown, feedback inhibition within NO/cGMP signaling (Figure 3). Within this feedback loop, cGMP bound to the regulatory GAF domain of PDE5 serves as a memory for the amount of NO the cell has been exposed to adjusting the subsequent cGMP response toward further incoming NO signals. Further experimental evidence is required to find out whether PDE5 activation is a general mechanism explaining the above described changes in the sensitivity of NO/cGMP signaling.

View larger version (33K): [in this window] [in a new window]   Figure 3. Feedback inhibition within the NO/cGMP signaling cascade in platelets. Increased cGMP levels lead to the direct activation of phosphodiesterase 5, which in turn degrades cGMP more rapidly. Phosphorylation of phosphodiesterase 5 by cGMP-dependent protein kinase increases its cGMP affinity. This feedback mechanism regulates the sensitivity of the NO/cGMP signaling cascade in platelets.

	Regulation of the Expression of NO-Sensitive GC

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
Parallel to the changed responsiveness of the cGMP signaling system, expressional regulation of NO-sensitive GC has been demonstrated by many groups. Variation of GC expression is conceivable in order to adapt to the amount of NO available under certain physiological or pathophysiological conditions. As a matter of fact, the development of nitrate tolerance may be based in part on downregulation of NO-sensitive GC. In line with this reasoning, various NO donors were reported to decrease the mRNA and protein levels of NO-sensitive GC in pulmonary artery cells by a cGMP-dependent mechanism.¹²¹ However, NO tolerance in humans was not paralleled by a changed GC content¹²² and, paradoxically, increased expression of both GC subunits was detected in blood vessels from NO-tolerant rats and rabbits.¹²³ It should be noted that both studies reported on a reduced phosphorylation of the downstream target of cGMP-dependent kinase, VASP. The reduced VASP phosphorylation under the condition of NO tolerance can be interpreted as switched-off NO/cGMP signaling caused by PDE activation (see earlier sections). There is a recent article on post-transcriptional regulation of the ₁ subunit of NO-sensitive GC in rat aorta.¹²⁴ The authors identified HuR (Human R, embryonic lethal abnormal visual [ELAV]-like RNA-binding protein) as a factor stabilizing GC ₁ mRNA. YC-1-induced activation of GC decreased HuR expression, thereby inducing rapid degradation of GC ₁ mRNA and lowering ₁ subunit expression as a negative feedback response.

Expression of GC subunits was also studied under conditions of low NO availability. Although animals in which NO production was impaired either by gene knockout¹¹⁰ or NO synthase inhibitor treatment¹²⁵ showed an enhanced sensitivity toward additional NO, aortic GC content was not found to be altered.¹¹⁰

Besides the availability of NO, the effects of various other conditions on GC expression have been studied. Hypertension and ageing appeared to be factors negatively influencing the expression of GC.^126–129 High salt intake by spontaneously hypertensive rats led to a reduced vascular GC content in the aorta, which was paralleled by impairment of the vascular relaxation response to NO donors.¹³⁰ Various additional factors like cytokines, estradiol, and ß-amyloid peptides appear to reduce GC protein.^131–134 Yet, also upregulation of aortic NO-sensitive GC in Wistar rats after myocardial infarction was reported.¹³⁵

	Putative Activators or Inhibitors

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
The issue of CO being a physiologically relevant activator of NO-sensitive GC has not convincingly been solved yet. CO was first shown to activate NO-sensitive GC approximately 4-fold in platelet supernatant.¹³⁶ Functionally, CO has been reported to influence smooth muscle tone, platelet aggregation, and neuronal signaling. CO is endogenously produced by the enzyme family of heme oxygenases in the process of heme degradation. The mechanism by which CO acts on NO-sensitive GC appears similar to that of NO: due to the high affinity for heme, CO binds to NO-sensitive GC under the formation of a hexa-coordinated carbonyl-heme complex.^43,137 However, in contrast to NO, CO does not induce the release of the histidine-to-iron bond. As breakage of this bond is prerequisite for GC activation, the lack of the transformation of the six- to the five-coordinated complex explains the rather poor GC-activating property of CO. Results with the novel GC activator YC-1 revitalized the idea of CO as an endogenous activator of NO-sensitive GC. In the presence of YC-1, CO stimulates NO-sensitive GC to the same extent as NO.^82,94 Yet, a possible physiological role of CO would require not only rather high CO concentrations but also an endogenously occurring YC-1-like substance. So far, evidence for such an endogenously occurring YC-1-like substance is missing. Furthermore, CO was suggested to negatively regulate NO stimulation of GC by competing for the heme group; however, this suggested inhibitory role appears unlikely because CO would have to be available at extremely high intracellular concentrations based on the over 1500-fold lower heme affinity compared with NO.¹³⁸

Before the identification NO as of the physiological stimulator of NO-sensitive GC, a multitude of mostly redox-active substances have been proposed as activators (see review¹⁵). Several mechanisms of activation have been postulated and subsumed as "redox regulation."¹³⁹ With respect to the small stimulatory potential of these compounds, their physiological role as activators appears minor. In addition, one has to consider that GC is very sensitive to NO and is even stimulated by the minute amounts NO present in the normal atmosphere. Therefore, many of the putative GC activators may act indirectly by increasing the amount of available NO in the solution, eg, by a reduction of the superoxide concentration thereby preventing the inactivation of NO to peroxynitrite.¹⁴⁰

Phosphorylation of NO-sensitive GC has been published by a few laboratories over the last 20 years. Enzymes possibly involved include PKC, PKA and PKG.^141–145 Further work will be needed to clarify the role of GC phosphorylation.

For many enzymes, product inhibition is a relevant mechanism of regulating catalytic activity. Accordingly, cGMP has been suggested to inhibit NO-sensitive GC.¹⁴⁶ However, the IC₅₀ values for cGMP were >5 mmol/L, concentrations that are unlikely to occur in vivo.

Moreover, calcium has been suggested to regulate the activity of NO-sensitive GC.^70,147,148 The calcium concentrations used to inhibit NO-sensitive GC in these studies (5 to 250 µmol/L) appear to be too high to assume a relevant role under physiological conditions. A recent report,¹⁴⁹ however, shows interesting data on a calcium-dependent membrane association of NO-sensitive GC. In human platelets, agonist-induced increase in free cytosolic calcium concentration was shown to lead to the translocation of NO-sensitive to the membrane accompanied by increased sensitivity toward NO. Whether these data apply as a general mechanism of regulating NO-sensitive GC will be evaluated in the near future.

	Conclusion and Perspective

Top Abstract Introduction Isoforms and Structure of... Prosthetic Heme Group Activation of NO-Sensitive GC... Mechanism of Activation Deactivation of NO-Sensitive GC Inhibitors Novel Activation Mechanisms of... Sensitization/Desensitization... Regulation of the Expression... Putative Activators or... Conclusion and Perspective References

 
Within the last years, new exciting structural and regulatory features of the well-established signaling enzyme NO-sensitive GC have been discovered. For the new isoform, ₂ß₁, a role in synaptic transmission is conceivable as this protein was shown to be mainly expressed in brain and to be targeted to synaptic membranes. In contrast, the ₁ß₁ heterodimer is prominent in vascularized tissues. Thus, the two GC isoforms differ in subcellular and tissue localization, which may reflect the association to the neuronal and endothelial NO synthases, respectively.

Furthermore, besides the physiological and pharmacological NO-based activation, two so far unknown routes to sensitize and stimulate the enzyme have been presented. The modulation of the NO responsiveness of NO-sensitive GC has important pharmacological implications for the therapy of cardiovascular diseases. The relevance of the respective substances has been already been substantiated in various animal models. A better understanding of the underlying molecular mechanisms will greatly improve our current knowledge of the enzyme, which in turn may also help to elucidate the physiology and pathophysiology of NO/cGMP signaling.

	Acknowledgments

 
This work was supported by the Deutsche Forschungsgemeinschaft DFG 1157/3-2.

	Footnotes

 
Original received March 6, 2003; revision received June 3, 2003; accepted June 5, 2003.

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