NO-Stimulated Guanylyl Cyclase
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This entry is adapted from the peer-reviewed paper 10.3390/cells12030471

NO-stimulated guanylyl cyclase (SGC) is a hemoprotein that plays key roles in various physiological functions. SGC is a typical enzyme-linked receptor that combines the functions of a sensor for NO gas and cGMP generator. SGC possesses exclusive selectivity for NO and exhibits a very fast binding of NO, which allows it to function as a sensitive NO receptor. 

nitric oxide stimulated guanylyl cyclase receptor

1. Cytosolic Guanylyl Cyclase Mediates Diverse Physiological Functions of NO

Nitric oxide (NO) is a gaseous diatomic molecule that acts as an intra- and extracellular messenger mediating diverse physiological and pathophysiological processes in various cells and tissues. NO exerts its function through two independent but overlapping pathways. One pathway relies on cGMP-dependent effector proteins, while another is cGMP-independent [1][2]. NO-stimulated guanylyl cyclase is an essential player in the NO/cGMP-signaling. This enzyme is often referred to as soluble guanylyl cyclase (SGC), due to its primarily cytosolic localization. Although multiple studies revealed that on many occasions, SGC is also found in membrane fractions of cell lysates and tissue homogenates [3][4], the term “SGC” remains most widely used. Soluble GC functions as a typical enzyme-linked receptor. Under resting conditions, SGC possesses weak cGMP-forming activity. However, following the binding of NO molecule to the SGC enzyme, cGMP-forming activity is activated several hundred-fold [5][6]. Elevated cellular cGMP level resulting from SGC activation engages cGMP-dependent kinases, phosphodiesterases, and cyclic nucleotide gated channels that affect a variety of cellular and physiological processes. These include calcium sequestration and cytoskeletal changes, relaxation of vascular smooth muscle cells (VSMC), improved oxygenation of tissues and organs [7], inhibition of adhesion and subsequent migration of leukocytes [8], reduction of platelet aggregation [9][10], facilitation of the repair of injured endothelium [11][12], inhibition of proliferation and migration of VSMCs [13], regulation of gastrointestinal motility [14], modulation of cancer development [15], and many others.

2. SGC Is a Highly Sensitive NO Receptor

SGC is a heterodimer which consists of one α and one β subunit. Humans and mice have two functional isoforms of the α subunit (α1 and α2) and one functional β1 isoform. The heterodimer α1β1 is ubiquitously expressed and has a higher level of expression. It has been recently classified as GC-1 [16]. The α2β1 heterodimer is classified as GC-2. GC-2 isoform is less abundant and is primarily expressed in the brain at the same level as the GC-1 counterpart. GC-2 is also detected in kidney and placenta. GC-1 and GC-2 are very similar in their structure and exhibit very similar responses to NO and other activating or inhibiting small molecules [17]. Nevertheless, there are some substantial differences in subcellular localization of GC-1 and GC-2. Ubiquitous GC-1 is mainly found in the cytosolic compartment of the cell, although a small fraction is membrane-associated [3]. In contrast, brain-expressed GC-2 isoform is primarily associated with the synaptic membrane [18], a property believed to be essential for neurotransmission [4][19].
The α and β subunits of SGC share a lot of sequence similarity and have similar domain organization. Each SGC subunit contains a heme nitric oxide/oxygen binding domain (H-NOX), a Per-Arnt-Sim domain (PAS), a coiled-coil domain (CC), and a catalytic domain (CAT). The β1 H-NOX domain harbors a heme prosthetic group [20], essential for binding the NO molecules. The structure of the α1β1 heterodimer established by cryogenic electron microscopy (cryo-EM) shows a two-lobe structure with the H-NOX/PAS domains on one connected by the CC domains end to the CAT domains on the other (Figure 1). Despite some differences between α1 and α2 sequences, the structure of the α2β1 isoform of SGC most likely follows the same fold.
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Figure 1. Structural changes of SGC in response to NO-dependent activation. (A): Schematic representation of the process of NO:-SGC adduct formation. The five-coordinate heme moiety of SGC (state a) binds NO to form a six-coordinate complex (state b). The six-coordinate complex subsequently converts irreversibly into a five-coordinate complex (state c) due to the rupture of Fe-His105 bond. Corresponding reaction rates are indicated. (B): Structural rearrangement of different SGC domains that occurs following NO binding causes significant activation of cGMP-forming activity.
Functional SGC is a hemoprotein containing a heme with ferrous iron. The heme moiety plays a key role in sensing the signal of elevated cellular NO levels. The heme is stabilized within the β1 H–NOX domain via coordination of the heme iron with His105 residue [6][21] and by interaction of the heme propionate groups with the Y135, Ser 137 and Arg 139 residues residing in the same domain [22][23]. The interaction of NO and SGC is a two-step process [24][25]. Initial binding of NO to the distal side of SGC heme results in the formation of a six-coordinate complex. However, unlike the stable complex between NO and heme in hemoglobin, the six-coordinate NO-heme complex of SGC is unstable. In a fraction of a second, the heme-His105 coordinate bond is disrupted (Figure 1A), maintaining only the NO-heme coordinate bond. The disruption of the His105-heme bond seems to release a conformational strain that triggers the relative rotation among α1 and β1 CC helices and straightening of the CC domains, while preserving some interactions between the β1 CC helix and the heme-containing β1 H-NOX domain (Figure 1B). The rotation of the CC helices causes a rotation of the catalytic CAT domains, resulting in changes in the GTP binding pocket [23][26]. These conformational changes only modestly lower the KM for the GTP substrate [27], but significantly increase the Vmax of the cGMP synthesis. Vmax of the high-cGMP output state induced by NO is several hundred times higher than of the resting non-stimulated state [28][29].
Many hemeproteins with histidine as a proximal ligand for heme evolved to sense gaseous diatomic ligands. Although the major physiological function of different globins, such as hemoglobin, myoglobin, or cytoglobins, is to serve as sensors and carriers of molecular oxygen (O2), these proteins are also capable of binding carbon monoxide (CO) and NO with high affinity. Unlike these gaseous sensors, SGC evolved to have a unique ligand selectivity. Studies performed with purified SGC demonstrated that it cannot bind O2 even under high pressure of pure O2 [30]. It has been reported that exposure of purified SGC to saturating amounts of CO results in a modest 2–4-fold elevation of cGMP-forming activity [6][31]. However, careful examinations of the reaction between purified GC1 and CO revealed that GC-1 isoform exhibit a low affinity for CO, with an estimated KD of 240–260 µM [30][32]. This value is more than four orders of magnitude higher than the estimated low nM level of physiological CO [33][34][35]. It seems unlikely that physiologically relevant CO-dependent activation of SGC takes place. The affinity of SGC for the NO ligand is much higher. Studies of interaction between purified GC-1 and NO solutions revealed a nanomolar affinity for NO (KD 54 nM) [30][36][37]. Since both SGC isoforms exhibit similar dose-dependent increase of cGMP-forming activity in response to NO donors [38], it is highly probable that the affinity for NO is very similar. Thus, SGC has a strong selectivity towards NO as the main physiological activating agent, as it is expected from a NO receptor. While the gaseous ligand selectivity of GC-1 and GC-2 was not compared, it is reasonable to assume that both SGC isoforms have similar affinities for signaling gasses.
However, if the affinity for NO is regarded as the main parameter determining the role of a protein as a highly sensitive NO receptor, SGC does not seem to fit the role. A number of intracellular histidine ligated hemoproteins have higher affinities for NO than SGC [39]. Thus, it is important to consider physiological levels of NO and SGC. Direct measurements of NO produced in different cells [40][41] and the assessment of bioavailable NO suggest that physiological levels of NO reach subnanomolar concentrations [40][42]. The EC50 values for various NO donors sufficient to elicit a desired physiological response is often in the range of 100 pM to 5 nM [40]. These are much lower values than the ~50 nM KD for NO determined in vitro with purified SGC. Thus, under normal physiological conditions, SGC encounters concentrations of NO much lower than its calculated KD value. Yet, these NO concentrations are sufficient to generate a physiological response. Therefore, the KD value determined at equilibrium and reflecting the affinity for NO is not an appropriate parameter to determine if SGC is an efficient NO receptor. Considering that the waves of NO generated by activated eNOS and nNOS are transient, these levels of NO are not sustained long to establish an equilibrium condition. Therefore, the NO binding constant is a parameter better suited to judge the effectiveness of SGC as NO receptor. While SGC’s affinity for NO is not the highest among known hemoproteins, the kinetics of NO binding to SGC heme is very fast. A number of studies directly measured the kinetics of NO interaction with SGC heme and determined the association constant kon to be in the 1.4–4.5 × 108 M−1s−1 range [24][29][30][43]. This is a diffusion-limited binding and the fastest NO binding among proteins known to interact with NO. Therefore, in a cellular environment containing many proteins competing for NO binding, the binding kinetics of NO to the ferrous SGC heme favors the formation of NO:SGC adduct and subsequent activation of cGMP-forming activity.
Once formed, the NO:SGC complex should be quite labile to be appropriate for various rapid signaling processes that depends on NO/cGMP signling. NO dissociation measured spectroscopically resulted in a half-life of the NO:SGC complex of approximately 2 min [44]. A similar half-life of approximately 3 min was reported in a different study [45]. These values obtained in vitro with purified SGC are not compatible with fast deactivation required for efficient NO signaling and observed experimentally. For example, studies performed on aortic rings demonstrated that relaxation of aortic rings can be re-elicited 1–2 min after previous exposure to NO [46]. This discrepancy most likely reflects the contribution of different cellular factors. In vitro spectroscopic studies demonstrated that some cellular factors may accelerate the process of NO:SGC decomposition. For example, in the presence of different thiols (DTT, GSH, cysteine) the half-life of the complex is much shorter than without thiols [45], while the addition of Mg2+-GTP yielded a half-life of 5 s [47]. Deactivation of NO:SGC determined by monitoring the decline in cGMP-forming activity yielded a similar ~5 s value for purified protein [48] and cytosolic fraction of bovine retina [49]. Even faster deactivation was reported in case of intact cerebellar cells, where the estimated half-life was 0.2 s [50].
Equally important for SGC function as an efficient NO receptor is the abundance of SGC protein in physiological systems responsive to NO. It has been estimated that intracellular concentrations of SGC, at least in platelets and cerebellar astrocytes, reaches micromolar range [51]. In mouse aorta, the amount of SGC far exceeds the amount needed to mediate the relaxation of aortic smooth muscles. The loss of functional GC-1 in mice lacking α1 SGC subunits was functionally compensated by GC-2 [52], which constitutes only 6% of the total SGC activity in aorta. The large excess of SGC over the bioavailable NO coupled with the fast-binding kinetics ensures that a sufficient number of SGC molecules is activated to achieve the desired physiological outcome.
In vitro studies with purified SGC heterodimer clearly demonstrate that the presence of Mg2+-GTP and NO is sufficient to promote NO-dependent activation of cGMP-forming activity. However, multiple data indicate that there is a number of cellular factors affecting either positively or negatively this process. For example, SGC has a higher sensitivity for NO [51][53] in intact cells than in vitro. The rate of NO dissociation from SGC heme in cerebellar cells is 25 times higher than the one observed in vitro with purified protein [50]. There is multiple evidence of SGC desensitization in vivo, but no desensitization is observed with the purified enzyme in vitro [54]. A number of studies reported that some cells contain factors affecting SGC activity. For example, the lysates of endothelial cells contain a heat-labile activator of SGC [55], while COS-7 cells contain factor(s) that strongly enhance the activity of resting and NO-activated purified SGC [56]. Studies of the last two and half decades demonstrated that SGC activity may be upregulated via allosteric modulation by synthetic small molecules. Two types of such allosteric regulators have been identified [57], namely SGC stimulators and SGC activators. Allosteric stimulators of SGC strongly potentiate NO signaling by sensitizing the enzyme to low doses of NO [57]. Many of these stimulators are undergoing clinical trials at different stages. At least two stimulators, riociguat and vericiguat, were approved as SGC-targeting therapeutics for the management of pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension [58][59], and heart failure conditions [60][61]. Allosteric activators seem to target the β1 H-NOX domain and activate NO-independently the enzyme that lacks heme or contains oxidized ferric heme [62]. They are also promising drug candidates [63]. The existence of such synthetic allosteric regulators suggests the potential existence of a cellular factor(s) that affect(s) the activity of SGC in a similar fashion.

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