Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Guanylyl Cyclase Receptors

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_434

Synonyms

 GC-A;  GC-B;  GC-C;  GC-D;  GC-G;  ret-GC;  sGC

Historical Background

In 1971 when Sutherland received the Nobel Prize for the discovery of the second messenger cAMP, the functions of cGMP were still a mystery, even though cGMP had been isolated from rat urine in 1963, and an enzyme that cleaved the phosphodiester bond was discovered the following year. The levels of cGMP are regulated by synthesis by guanylyl cyclases (GCs), extrusion from the cell, and/or degradation by phosphodiesterases (Kots et al. 2009).

GCs were discovered, 6 years after the cGMP was identified, by three separate groups (Hardman and Sutherland 1969; Schultz et al. 1969; White and Aurbach 1969). Two classes of GCs, one that is cytosolic (soluble) and the other that is found associated with the particulate or membrane fraction of cells could be identified. The two forms of guanylyl cyclases are composed of polypeptides of different sizes, with different biochemical properties (Kimura and Murad 1974) (Fig. 1).
Guanylyl Cyclase Receptors, Fig. 1

Schematic of the domain organization of receptor guanylyl cyclases. Shown also is the topology of the enzymes discussed in this article either being present in the membrane of the cell or in the cytosol. Membrane-associated GCs are shown as dimers, though there is evidence that they can oligomerize in cells. Receptor GCs can exist as dimers even in the absence of their respective ligands

Soluble Guanylyl Cyclases

The soluble guanylyl cyclases (sGC) are heterodimers of two dissimilar subunits, alpha and beta. There are four types of alpha subunits, namely, α1, α2, α3, and α2 i, and three types of beta subunits, namely, β1, β2, and β3. The ubiquitously expressed α1/ß1 dimer is the predominant complex, with highest levels of mRNA in brain, lung, heart, kidney, spleen, and muscle (Russwurm and Koesling 2002; Mergia et al. 2009). All the heterodimers are active, albeit to varying extents, except those containing α2 i. The α2 i is a splice variant of α2 and provides a mechanism for regulating the activity of the α2/β1 form of sGC by acting as a dominant negative protein in cells. However, active homodimers in lower organisms have also been reported (Morton et al. 2005).

The crystal structure of the sGC from the green algae Chlamydomonas reinhardtii has been solved (Winger et al. 2008) and the structure of the catalytic domain of human sGC has been solved (Allerston et al. 2013). There is also a report on the crystal structure of Cya2, a prokaryotic guanylyl cyclase from cyanobacterium Synechocystis PCC6803 (Rauch et al. 2008).

The sGCs are ubiquitously expressed and are responsible for smooth muscle relaxation, neurotransmission, and inhibition of platelet migration (Kots et al. 2009) and can be stimulated by free radicals, nitrovasodilators, and similar molecules. Nitric oxide (NO), the major ligand for sGC, binds to the N-terminal heme-binding H-NOX domain. In the absence of NO, the iron atom of the heme moiety bonds with a histidine residue present in the protein, keeping the cyclase domain inactivate. NO binding to the heme moiety leads to the disruption of this interaction, altering the conformation of the enzyme, thereby resulting in its activation. NO binds to ferrous (Fe2+) heme iron in the H-NOX domain of the resting sGC to activate it (Stone and Marletta 1996; Zhao et al. 1999); however, oxidized ferric (Fe3+) heme iron strongly attenuates the enzymatic response to NO (Zhao et al. 2000; Schrammel et al. 1996). A number of conserved cysteine residues in the alpha and beta subunits have been identified, and covalent modification of three cysteine residues (two in the alpha subunit and one in beta subunit) by S-nitrosation or S-nitrosylation has also been shown to affect sGC desentisization to NO stimulation (Beuve et al. 2016). Protoporphyrin IX can bind to and activate sGCs independent of heme or NO (Lucas et al. 2000). Carbon monoxide also regulates sGCs in a manner similar to that of NO, although its affinity for the enzyme is much lower than that of NO. ATP allosterically inhibits the activity of the soluble guanylyl cyclase (Derbyshire et al. 2009).

The C-terminal cyclase domains in each subunit are connected to the N-terminus by a linker region which contributes to the dimerization of sGC. Since the α-subunits of sGCs lack the critical residues required for catalytic activity, they heterodimerize with the β-subunits to give rise to a functional active site (Lucas et al. 2000; Perkins 2006).

Membrane-Associated Guanylyl Cyclases

Seven classes of membrane-associated guanylyl cyclases have been characterized. They are GC-A, GC-B, GC-C, GC-D, and GC-G, and the retinal GCs, GC-E, and GC-F. All the receptor guanylyl cyclases share a common domain organization with a single-pass transmembrane region. They have an extra cellular domain (ECD), the amino acid sequence of which is poorly conserved across the different classes, thereby imparting ligand specificity. This domain is followed by a transmembrane domain and an intracellular domain (ICD). The ICD is comprised of a juxtamembrane domain followed by a regulatory kinase homology domain (KHD) which binds ATP. Following the KHD is a linker region which connects to the guanylyl cyclase domain. Ligand binding to the extracellular domains results in receptor activation and increased production of cGMP in the cell. Classical membrane-bound GCs are often devoid of kinase activity (Potter 2011a), perhaps because of the absence of a glutamate residue in the KHD domain that is important for the phosphotransfer reaction (Potter 2005). However, a novel class of membrane-associated GC-linked receptor kinases (currently four members), possessing both intrinsic kinase and GC activity, with the GC catalytic center being encapsulated within an active kinase domain, was unearthed using homology-guided bioinformatic data mining tools designed from annotated amino acid residues in the GC catalytic centers of lower eukaryotes. (Kwezi et al. 2007; Kwezi et al. 2011; Meier et al. 2010; Qi et al. 2010).

The Natriuretic Peptide Family Receptors

These comprise three receptors, namely, Natriuretic Peptide Receptors A, B, and C. The ligands for these receptors are natriuretic peptides – atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP).

Guanylyl Cyclase A/Natriuretic Peptide Receptor A (GC-A/NPR-A)

The mammalian cDNA encoding guanylyl cyclase A (NPR-A) was identified using the gene sequence of the sea urchin particulate guanylyl cyclase receptor as a probe to screen a cDNA library (Kots et al. 2009). NPR-A preferentially binds ANP and BNP. NPR-A is found in the heart, kidney, adrenal cortex, and vasculature.

Vasodilation and natriuresis are the most commonly studied aspects of signaling via NPR-A. GC-A prevents hypertrophy of the heart by relaxing the vascular musculature, thereby reducing the cardiac output. In kidneys, NPR-A assists in the secretion of sodium and reduction of aldosterone secretion by the adrenal cortex, thus reducing blood pressure (Martel et al. 2010).

Transcription of NPR-A is regulated by Sp1. NPR-A has been shown to downregulate its own expression by a feedback inhibition loop via a cGMP response element. Alternative splice variants of NPR-A can heterodimerize (Martel et al. 2010). The juxtamembrane domain in NPR-A has been shown to modulate the proteolytic cleavage of the ECD, thereby regulating its activity (Huo et al. 1999). Posttranslational modifications which include glycosylation are implicated in the folding of NPR-A and its trafficking to the surface of the cells. The receptor is highly phosphorylated on eight serine and threonine residues within the KHD. When activated by its ligands, NPR-A is deposphorylated, which then attenuates the activation by the ligand, leading to desensitization and signal downregulation (Koller et al. 1993). Five of the eight total phosphorylation sites are conserved in GC-A and GC-B (Potter 2011). Chronic exposure to high concentrations of their ligands (homologous desensitization) or exposure to growth hormones such as angiotensin II (ANG II) and endothelin (heterologous desensitization) are reported to lead to attenuation of the receptor (Potter 2011). Imbalance in circulating levels of natriuretic peptides and expression of NPR-A receptor is seen in hypertensive mice, making this receptor a potential target for gene therapy (Martel et al. 2010).

Guanylyl Cyclase B/Natriuretic Peptide Receptor B (GC-B/NPR-B)

Using the sequence of NPR-A, NPR-B was cloned from rat brain cDNA and human placenta. NPR-B is primarily located in the pituitary gland, adrenal gland, ovary, endothelium, vascular smooth muscle, and kidney (Schulz 2005). NPR-B binds CNP with highest affinity amongst the natriuretic peptides. Apart from the relaxation of the heart and lowering of blood pressure, NPR-B signaling also relaxes the smooth muscle of the oviduct, colon, and trachea. In the brain, CNP and NPR-B play a role in gonadotropin secretion. Expression of NPR-B in the ovary and testis may be responsible for development of mature ovarian follicles and regulation of sperm transport by relaxing the seminiferous tubules. NPR-B also promotes bone development and causes skeletal overgrowth on overexpression (Schulz 2005).

No cGMP response element has been identified in the NPR-B promoter (Martel et al. 2010). In NPR-B, glycosylation may play a role in ligand binding (Schulz 2005).

Like NPR-A, phosphorylation of the serine and threonine is required for peptide activation, and prolonged exposure with the natriuretic peptide (homologous desensitization) as well as platelet-derived growth factor, fibroblast growth factor, or serum or acute exposure to phorbol esters or calcium-elevating agents (heterologous desensitization) leads to dephosphorylation and inactivation of the receptor (Potter 2011; Dickey et al. 2010). The lack of an intact KHD in NPR-B causes stunted skeletal growth in humans, and splice variants of NPR-B lacking the KHD or intracellular domains are inactive and can act as dominant negatives, hindering bone development (Hachiya et al. 2007). Homozygous loss-of-function mutations in GC-B have been identified to cause acromesomelic dysplasia, a rare form of short-limbed dwarfism in human patients (Bartels et al. 2004).

Only one other protein has been identified which binds all the natriuretic peptides, the NPR-C receptor. This receptor has no guanylyl cyclase activity as it lacks the intracellular domain. NPR-C is expressed in the heart, lung, vascular smooth muscle cells, kidney glomeruli, adrenal gland, brain cortex, and pituitary gland (Martel et al. 2010). The primary function of the NPR-C receptor was thought to be sequestration and metabolic clearance of natriuretic peptides and it was therefore designated as the clearance receptor. The 37 amino acid long cytoplasmic tail of NPR-C has been shown to mediate inhibition of adenylyl cyclase activity on ligand binding to the receptor (Anand-Srivastava 2005).

Guanylyl Cyclase C (GC-C)

Guanylyl cyclase C (GC-C) is the third member of the family of receptor guanylyl cyclases that was identified. It was identified as the receptor for the bacterial heat-stable enterotoxin peptides produced by pathogenic strains of Escherichia coli (Schulz et al. 1990). GC-C is predominantly expressed in the intestinal tract.

Endogenous ligands for GC-C are guanylin and uroguanylin and have been purified from intestinal mucosa and urine. They are cysteine-rich peptides, similar to the stable toxin peptide, but, they have a 10–100-fold lower affinity for GC-C. It is believed that they regulate intestinal fluid and ion transport. Activation of GC-C, following binding of its ligands, results in increased synthesis cGMP. Accumulation of intracellular cGMP activates cyclic nucleotide-dependent protein kinases, PKA and PKG, leading to the phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) and increased chloride secretion through CFTR. Ion efflux leads to increased fluid secretion from the cell, resulting in a watery diarrhea. This manifests as traveler’s diarrhea in adults which is self-limiting but may be fatal in infants (Basu et al. 2010). Recently, missense mutation, in them were identified. Individuals harboring this mutation show mild or severe forms of congenital or familiar secretory diarrhea (Fiskerstrand et al. 2012; Muller et al. 2015). These mutations resulted in hyperresponsiveness to ligand stimulation, with subsequent enhanced intracellular accumulation of cGMP. Also, homozygous inhibitory mutations in GUCY2C, attenuating or abolishing GC-C activity, are also reported, leading to neonatal meconium ileus and obstruction of the small intestine by thick mucoid stools in two unrelated Bedouin children (Romi et al. 2012).

GC-C prexists as an oligomer in the absence of ligand. GC-C is differentially glycosylated, and glycosylation is important for the binding of ligands to GC-C, as well as trafficking of GC-C to the cells membrane (Arshad et al. 2013; Hasegawa et al. 1999). GC-C is a substrate for inhibitory phosphorylation by c-src, resulting in reduced ligand-mediated cGMP production. Phosphorylation of a serine residue in the C-terminus by protein kinase C results in potentiation of ligand-stimulated activity in vivo and in vitro. Prolonged exposure of GC-C to its ligands leads to cell-specific desensitization of the receptor, by mechanisms that are not clearly understood at present. Intestine and kidney-enriched PDZ protein (IKEPP) and c-src are the only proteins to be identified that interact with GC-C and regulate its activity (Basu et al. 2010).

The involvement of intestinal (uro)guanylin/GC-C pathway in regulation of epithelial functions other than ion transport have also been identified. Loss in the gene expression of the paracrine hormones guanylin and uroguanylin has been reported in colorectal carcinogenesis (Wilson et al. 2014). Increased intestinal tumor initiation and growth on mutation in Apc or upon exposure to the carcinogen azoxymethane in GC-C-deficient mice (Li et al. 2007) was observed. The ligands for GC-C have been shown to have a cytostatic effect on intestinal cells and thereby act as a barrier to tumorogenesis. Also, binding of c-src via the SH2 region to phosphorylated GC-C contributes to enhanced intestinal cell proliferation and dedifferentiation in cultured intestinal tumor cell lines (Basu et al. 2009). Several downstream signaling pathways have been identified to modulate GC-C-mediated colonic cell cytostasis, such as inhibition of oncogenic Akt signaling (Lin et al. 2010), reduced expression of cell cycle drivers including β-catenin, cyclin D1, pRb, increased expression of cell cycle inhibitors including p27 (Blomain et al. 2013), and the upregulation of p21 resulting in cellular cytostasis and senescence (Basu et al. 2014).

GC-C is highly expressed in the intestine and is evolutionarily preserved. The GC-C knockout mouse have been reported to show hyperphagy resulting in obesity (Valentino et al. 2011). However, in another recent study reported that GC-C knockout mice have normal body weight, adiposity, and glucose tolerance (Begg et al. 2014). The mice were however resistant to stable toxin-mediated diarrhea. GC-C knockout mice were also reported to exhibit hyperactivity and attention deficit disorders (Gong et al. 2011).

Guanylyl Cyclase D (GC-D)

Canonical olfactory signaling occurs when cyclic nucleotide gated (CNG) ion channel are activated by cAMP in the olfactory neurons. When it was discovered that odorants triggered cGMP production, which activated a cGMP-gated ion channel, the olfactory guanylyl cyclase GC-D was identified. This gene is found to be well conserved in rodents and canines, but is a pseudogene in a number of primate species, including the human (GC-E). A very small subset of the olfactory sensory neurons (OSN) of mice expresses GC-D, and these neurons terminate in necklace glomeruli (Zufall and Munger 2010). Nonprimates detect more olfactory cues than primates, and may even detect pheromones via GC-D (Young et al. 2007). Recent reports suggest that uroguanylin and/or guanylin can activate GC-D.

GC-D can also be activated by bicarbonate ions which are produced by carbonic anhydrase specifically expressed in the GC-D subset of OSNs. Reports have shown that rodents can be trained to avoid CO2 concentrations as low at 0.5%. It is speculated that this is a means to detect other animals in the vicinity. There is also evidence that guanylyl cyclase activating protein (GCAP1) could also modulate a calcium-dependent activation of GC-D (Zufall and Munger 2010).

Retinal Guanylyl Cyclases: Guanylyl Cyclase E/F (GC-E/F)

In the mid-1990s, membrane-bound receptor guanylyl cyclases were identified in bovine photoreceptors. A gene encoding a particulate guanylyl cyclase was isolated from retinal cDNA based on its similarity to previously characterized GCs (Shyjan et al. 1992). This gene is referred to as retGC1 or retGC2 in humans or GC-E/GC-F in other mammals. RetGC2 is exclusively expressed in the retina while expression of retGC1 is seen in the pineal gland and retina. The mRNA of retGC1 has been detected in the olfactory bulb of fish, cochlear nerve and organ of Corti (Hunt et al. 2010).

GC-E and GC-F are important in retinal phototransduction and regulate the opening and closure of cGMP-gated ion channels. These channels are open in the dark and close on perception of light. The loss of either retGC results in compromised visual signal transduction suggesting that both retGCs are necessary for normal phototransduction.

The retGCs are orphan receptors as no ligands for the ECD have been discovered till date. These receptors are regulated by proteins which associate with their intracellular domains. Guanylate cyclase activating proteins (GCAPs) are always found associated with the retGCs. In resting depolarized cells, GCAPs are bound by Ca2+ ions which prevent activation of retGC. Upon light stimulus, the cGMP-specific phosphodiesterase, PDE6, found in photoreceptor cells is activated and degrades cGMP present in the cell, leading to closure of the CNG, thereby decreasing Ca2+ levels in the now hyperpolarized cell. The Ca2+ ions dissociate from GCAP, permitting them to activate retGC. Cyclic GMP levels are now elevated resulting in the reopening of the ion channels and reversion of the cell to a depolarized state.

Despite the importance of both retGCs for visual signal transduction in mice, visual impairments studied so far in humans map only to the retGC1 locus. Recessive mutations in retGC1 are a major cause of Leber congenital amaurosis (LCA). Retinitis pigmentosa also is caused by a mutation in GC1. Other mutations in retGC1 are responsible for 35% of all rod-cone dystrophies (Hunt et al. 2010).

Guanylyl Cyclase G (GC-G)

The GC-G is an orphan receptor and transcripts have been found in mouse testis, kidney, and in the Grueneberg ganglion (Lin et al. 2008). This receptor may play a role in thermo-sensation, a process which has been shown to be via cGMP signaling in C. elegans (Zufall and Munger 2010). GC-G receptor is absent in humans.

Summary

Almost 50 years after the discovery of cGMP, its function in vision, olfaction, vasodilatation, and fluid ion homeostasis has been established. A number of guanylyl cyclases have been identified and characterized but questions still remain as to the ligands and exact functions of some of the receptors. The complex domain organization of these receptor guanylyl cyclases indicate that they may be regulated in multiple ways and be involved in crosstalk with other signaling pathways, and studies along these lines will be of interest in future.

References

  1. Allerston CK, von Delft F, Gileadi O. Crystal structures of the catalytic domain of human soluble guanylate cyclase. PLoS One. 2013;8:e57644.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Anand-Srivastava MB. Natriuretic peptide receptor-C signaling and regulation. Peptides. 2005;26:1044–59.PubMedCrossRefGoogle Scholar
  3. Arshad N, Ballal S, Visweswariah SS. Site-specific N-linked glycosylation of receptor guanylyl cyclase C regulates ligand binding, ligand-mediated activation and interaction with vesicular integral membrane protein 36, VIP36. J Biol Chem. 2013;288:3907.PubMedCrossRefGoogle Scholar
  4. Bartels CF, Bukulmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C, Pauli RM, Mundlos S, Chitayat D, Shih LY, Al-Gazali LI, Kant S, Cole T, Morton J, Cormier-Daire V, Faivre L, Lees M, Kirk J, Mortier GR, Leroy J, Zabel B, Kim CA, Crow Y, Braverman NE, van den Akker F, Warman MLA. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet. 2004;75(1):27–34.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Basu N, Bhandari R, Natarajan VT, Visweswariah SS. Cross talk between receptor guanylyl cyclase C and c-src tyrosine kinase regulates colon cancer cell cytostasis. Mol Cell Biol. 2009;29:5277–89.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Basu N, Arshad N, Visweswariah SS. Receptor guanylyl cyclase C (GC-C): regulation and signal transduction. Mol Cell Biochem. 2010;334:67–80.PubMedCrossRefGoogle Scholar
  7. Basu N, Saha S, Khan I, Ramachandra SG, Visweswariah SS. Intestinal cell proliferation and senescence are regulated by receptor Guanylyl Cyclase C and p21. J Biol Chem. 2014;89:581–93.CrossRefGoogle Scholar
  8. Begg DP, Steinbrecher KA, Mul JD, Chambers AP, Kohli R, Haller A, Cohen MB, Woods SC, Seeley RJ. Effect of guanylate cyclase-c activity on energy and glucose homeostasis. Diabetes. 2014;63(11):3798–804.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Beuve A, Wu C, Cui C, Liu T, Jain MR, Huang C, Yan L, Kholodovych V, Li H. Identification of novel S-nitrosation sites in soluble guanylyl cyclase, the nitric oxide receptor. J Proteome. 2016;s138:40–7.CrossRefGoogle Scholar
  10. Blomain ES, Lin JE, Kraft CL, Trela UT, Rock JM, Aing AS, Snook AE, Waldman SA. Translating colorectal cancer prevention through the guanylyl cyclase C signaling axis. Expert Rev Clin Pharmacol. 2013;6:557–64.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Derbyshire ER, Fernhoff NB, Deng S, et al. Nucleotide regulation of soluble guanylate cyclase substrate specificity. Biochemistry. 2009;48:7519–24.PubMedCrossRefPubMedCentralGoogle Scholar
  12. Dickey DM, Barbieri KA, McGuirk CM, Potter LR. Mol Pharmacol. 2010;78:431–5.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Fiskerstrand T, Arshad N, Haukanes BI, Tronstad RR, Pham KD, Johansson S, Havik B, Tonder SL, Levy SE, Brackman D, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS, Knappskog PM. Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med. 2012;366:1586–95.PubMedCrossRefGoogle Scholar
  14. Gong R, Ding C, Hu J, Lu Y, Liu F, Mann E, Xu F, Cohen MB, Luo M. Role for the membrane receptor guanylyl cyclase-C in attention deficiency and hyperactive behavior. Science. 2011;333:1642–6.PubMedCrossRefGoogle Scholar
  15. Hachiya R, Ohashi Y, Kamei Y, et al. Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development. J Clin Endocrinol Metab. 2007;92:4009–14.PubMedCrossRefGoogle Scholar
  16. Hardman JG, Sutherland EW. Guanyl cyclase, an enzyme catalyzing the formation of guanosine 3′,5′-monophosphate from guanosine trihosphate. J Biol Chem. 1969;244:6363–70.PubMedPubMedCentralGoogle Scholar
  17. Hasegawa M, Hidaka Y, Wada A, Hirayama T, Shimonishi Y. The relevance of N-linked glycosylation to the binding of a ligand to guanylate cyclase C. Eur J Biochem. 1999;263:338–46.PubMedCrossRefGoogle Scholar
  18. Hunt DM, Buch P, Michaelides M. Guanylate cyclases and associated activator proteins in retinal disease. Mol Cell Biochem. 2010;334:157–68.PubMedCrossRefGoogle Scholar
  19. Huo X, Abe T, Misono KS. Ligand binding-dependent limited proteolysis of the atrial natriuretic peptide receptor: juxtamembrane hinge structure essential for transmembrane signal transduction. Biochemistry. 1999;38:16941–51.PubMedCrossRefGoogle Scholar
  20. Kimura H, Murad F. Evidence for two different forms of guanylate cyclase in rat heart. J Biol Chem. 1974;249:6910–6.PubMedPubMedCentralGoogle Scholar
  21. Koller KJ, Lipari MT, Goeddel DV. Proper glycosylation and phosphorylation of the type A natriuretic peptide receptor are required for hormone-stimulated guanylyl cyclase activity. J Biol Chem. 1993;268:5997–6003.PubMedGoogle Scholar
  22. Kots AY, Martin E, Sharina IG, et al. A short history of cGMP, guanylyl cyclases, and cGMP-dependent protein kinases. Handb Exp Pharmacol. 2009;19:1–14.Google Scholar
  23. Kwezi L, Meier S, Mungur L, Ruzvidzo O, Irving H, Gehring C. The Arabidopsis thaliana brassinosteroid receptor (AtBRI1) contains a domain that functions as a guanylyl cyclase in vitro. PLoS One. 2007;2:e449.PubMedCrossRefPubMedCentralGoogle Scholar
  24. Kwezi LI, Ruzvidzo O, Wheeler JI, Govender K, Iacuone S, Thompson PE, Gehring C, Irving HR. The phytosulfokine (PSK) receptor is capable of guanylate cyclase activity and enabling cyclic GMP dependant signaling in plants. J Biol Chem. 2011;286:22580–8.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Lin H, Cheng CF, Hou HH, et al. Disruption of guanylyl cyclase-G protects against acute renal injury. J Am Soc Nephrol. 2008;19:339–48.PubMedCrossRefPubMedCentralGoogle Scholar
  26. Lin JE, Li P, Snook AE, Schulz S, Dasgupta A, Hyslop TM, Gibbons AV, Marszlowicz G, Pitari GM, Waldman SA. The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology. 2010;138:241–54.PubMedCrossRefGoogle Scholar
  27. Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y, Baran AA, Siracusa LD, Pitari GM, Waldman SA. Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology. 2007;133:599–607.PubMedCrossRefGoogle Scholar
  28. Lucas KA, Pitari GM, Kazerounian S, et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev. 2000;52:375–414.PubMedPubMedCentralGoogle Scholar
  29. Martel G, Hamet P, Tremblay J. Central role of guanylyl cyclase in natriuretic peptide signaling in hypertension and metabolic syndrome. Mol Cell Biochem. 2010;334:53–65.PubMedCrossRefGoogle Scholar
  30. Meier S, Ruzvidzo O, Morse M, Donaldson L, Kwezi L, Gehring C. The Arabidopsis wall associated kinase-like 10 gene encodes a functional guanylyl cyclase and is co-expressed with pathogen defense related genes. PLoS One. 2010;5:e8904.PubMedCrossRefPubMedCentralGoogle Scholar
  31. Mergia E, Koesling D, Friebe A. Genetic mouse models of the NO receptor ‘soluble’ guanylyl cyclases. Handb Exp Pharmacol. 2009;191:33–46.CrossRefGoogle Scholar
  32. Morton DB, Langlais KK, Stewart JA, Vermehren A. Comparison of the properties of the five soluble guanylyl cyclase subunits in Drosophila melanogaster. J Insect Sci. 2005;5:12.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Muller T, Rasool I, Heinz-Erian P, Mildenberger E, Hulstrunk C, Muller A, Michaud L, Koot BG, Ballauff A, Vodopiutz J, Rosipal S, Petersen BS, Franke A, Fuchs I, Witt H, Zoller H, Janecke AR, Visweswariah SS. Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C. Gut. 2015;65:1306–13.PubMedCrossRefPubMedCentralGoogle Scholar
  34. Perkins WJ. Regulation of soluble guanylyl cyclase: looking beyond NO. Am J Physiol Lung Cell Mol Physiol. 2006;291:L334–6.PubMedCrossRefGoogle Scholar
  35. Potter LR. Domain analysis of human transmembrane guanylyl cyclase receptors: implications for regulation. Front Biosci. 2005;10:1205–20.PubMedCrossRefGoogle Scholar
  36. Potter LR. Guanylyl cyclase structure, function and regulation. Cell Signal. 2011a;23:1921–6.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Potter LR. Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases. Pharmacol Ther. 2011b;130:71–82.PubMedCrossRefGoogle Scholar
  38. Qi Z, Verma R, Gehring C, Yamaguchi Y, Zhao Y, Ryan CA, Berkowitz GA. Ca2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca2+ channels. Proc Natl Acad Sci USA. 2010;107:21193–8.PubMedCrossRefPubMedCentralGoogle Scholar
  39. Rauch A, Leipelt M, Russwurm M, et al. Crystal structure of the guanylyl cyclase Cya2. Proc Natl Acad Sci USA. 2008;105:15720–5.PubMedCrossRefPubMedCentralGoogle Scholar
  40. Romi H, Cohen I, Landau D, Alkrinawi S, Yerushalmi B, Hershkovitz R, NewmanHeiman N, Cutting GR, Ofir R, Sivan S, Birk OS. Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. Am J Hum Genet. 2012;90:893–9.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Russwurm M, Koesling D. Isoforms of NO-sensitive guanylyl cyclase. Mol Cell Biochem. 2002;230:159–64.PubMedCrossRefGoogle Scholar
  42. Schrammel A, Behrends S, Schmidt K, Koesling D, Mayer B. Characterization of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one as a heme-site inhibitor of nitric oxide-sensitive guanylyl cyclase. Mol Pharmacol. 1996;50:1–5.PubMedPubMedCentralGoogle Scholar
  43. Schultz G, Böhme E, Munske K. Guanyl cyclase: determination of enzyme activity. Life Sci. 1969;8:1323–32.PubMedCrossRefGoogle Scholar
  44. Schulz S, Green CK, Yuen PS, et al. Guanylyl cyclase is a heat-stable enterotoxin receptor. Cell. 1990;63:941–8.PubMedCrossRefGoogle Scholar
  45. Schulz S. C-type natriuretic peptide and guanylyl cyclase B receptor. Peptides. 2005;26:1024–34.PubMedCrossRefGoogle Scholar
  46. Shyjan AW, de Sauvage FJ, Gillett NA, et al. Molecular cloning of a retina-specific membrane guanylyl cyclase. Neuron. 1992;9:727–37.PubMedCrossRefGoogle Scholar
  47. Stone JR, Marletta MA. Spectral and kinetic studies on the activation of soluble guanylate cyclase by nitric oxide. Biochemistry. 1996;35:1093–9.PubMedCrossRefGoogle Scholar
  48. Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS, Hyslop T, Schulz S, Waldman SA. A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. J Clin Invest. 2011;121(9):3578–88.PubMedCrossRefPubMedCentralGoogle Scholar
  49. White AA, Aurbach GD. Detection of guanyl cyclase in mammalian tissues. Biochim Biophys Acta. 1969;191:686–97.PubMedCrossRefGoogle Scholar
  50. Winger JA, Derbyshire ER, Lamers MH, et al. The crystal structure of the catalytic domain of a eukaryotic guanylate cyclase. BMC Struct Biol. 2008;8:42.PubMedCrossRefPubMedCentralGoogle Scholar
  51. Wilson C, Lin JE, Li P, Snook AE, Gong J, Sato T, Liu C, Girondo MA, Rui H, Hyslop T, Waldman SA. The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. Cancer Epidemiol Biomark Prev. 2014;23(11):2328–37.CrossRefGoogle Scholar
  52. Young JM, Waters H, Dong C, et al. Degeneration of the olfactory guanylyl cyclase D gene during primate evolution. PLoS One. 2007;2:e884.PubMedCrossRefPubMedCentralGoogle Scholar
  53. Zhao Y, Brandish PE, Ballou DP, Marletta MA. A molecular basis for nitric oxide sensing by soluble guanylate cyclase. Proc Natl Acad Sci USA. 1999;96(26):14753–8.PubMedCrossRefPubMedCentralGoogle Scholar
  54. Zhao Y, Brandish PE, DiValentin M, Schelvis JP, Babcock GT, Marletta MA. Inhibition of soluble guanylate cyclase by ODQ. Biochemistry. 2000;39(35):10848–54.PubMedCrossRefGoogle Scholar
  55. Zufall F, Munger SD. Receptor guanylyl cyclases in mammalian olfactory function. Mol Cell Biochem. 2010;334(1–2):191–7.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular Reproduction, Development and GeneticsIndian Institute of ScienceBangaloreIndia