Journal articles: 'Receptor guanylyl cyclase C'

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Mann, E. A., M. B. Cohen, and R. A. Giannella. "Comparison of receptors for Escherichia coli heat-stable enterotoxin: novel receptor present in IEC-6 cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 1 (January 1, 1993): G172—G178. http://dx.doi.org/10.1152/ajpgi.1993.264.1.g172.

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Enterotoxigenic Escherichia coli elaborate a heat-stable enterotoxin that causes diarrhea in humans and animals. The primary event in the diarrheal cascade is the binding of this enterotoxin to specific receptors on enterocytes and activation of guanylyl cyclase. Two intestinal cell lines, Caco-2 and IEC-6, were tested for the presence of these receptors. Although both cell lines exhibited specific binding, only the Caco-2 cell line responded to heat-stable enterotoxin with increased guanylyl cyclase activity. Cloning and expression studies confirmed that the receptor present in Caco-2 cells is a homologue of guanylyl cyclase C, a known transmembrane heat-stable enterotoxin receptor. Expression of the receptor in differentiating Caco-2 cells increases with cell maturation, indicating that these cells are a suitable model for future studies. However, Northern and polymerase chain reaction analyses demonstrated that guanylyl cyclase C is not expressed in IEC-6 cells, strongly suggesting the presence of a novel heat-stable enterotoxin receptor that is not coupled to guanylyl cyclase activity.

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Trachte, G. J., S. Kanwal, B. J. Elmquist, and R. J. Ziegler. "C-type natriuretic peptide neuromodulates via "clearance" receptors." American Journal of Physiology-Cell Physiology 268, no. 4 (April 1, 1995): C978—C984. http://dx.doi.org/10.1152/ajpcell.1995.268.4.c978.

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A recently discovered endogenous autacoid, C-type natriuretic peptide, was tested in a pheochromocytoma (PC12) cell line for effects on 1) catecholamine release induced by a depolarizing stimulus, 2) guanylyl and adenylyl cyclase activities, and 3) specific 125I-labeled atrial natriuretic peptide (ANP) binding. C-type natriuretic peptide suppressed evoked neurotransmitter release in the absence of guanylyl cyclase activation or adenylyl cyclase inhibition; however, both a "clearance" (ANP-C) receptor binding agent, des-[Gln18Ser19Gly20Leu21Gly22]-ANF-(4-23)-NH2 (cANF), and pertussis toxin prevented this neuromodulatory effect. The C-type natriuretic peptide preferentially bound to receptors that also bound cANF. The results suggest that C-type natriuretic peptide suppressed evoked neurotransmitter efflux by binding to ANP-C receptors coupled to a pertussis toxin-sensitive process; furthermore, the neuromodulatory effect of C-type natriuretic peptide occurred independently of guanylyl cyclase activation or adenylyl cyclase inhibition. The novel aspects of these findings are 1) neuromodulatory effects of C-type natriuretic peptide, 2) guanylyl cyclase-independent actions of C-type natriuretic peptide, and 3) ANP-C receptors mediating C-type natriuretic peptide actions.

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Bhandari, Rashna, K. Suguna, and Sandhya S. Visweswariah. "Guanylyl Cyclase C Receptor: Regulation of Catalytic Activity by ATP." Bioscience Reports 19, no. 3 (June 1, 1999): 179–88. http://dx.doi.org/10.1023/a:1020273619211.

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Guanylyl cyclase C (GCC), a member of the family of membrane bound guanylyl cyclases is the receptor for the heat-stable enterotoxin (ST) peptides and the guanylin family of endogenous peptides. GCC is activated upon ligand binding to increase intracellular cGMP levels, which in turn activates other downstream signalling events in the cell. GCC is also activated in vitro by nonionic detergents. We have used the T84 cell line as a model system to investigate the regulation of GCC activity by ATP. Ligand-stimulated GCC activity is potentiated in the presence of ATP, whereas detergent-stimulated activity is inhibited. The potentiation of GCC activity by ATP is dependent on the presence of Mg2+ ions, and is probably brought about by a direct binding of Mg-ATP to GCC. The protein kinase-like domain of GCC, which has earlier been shown to play a critical role in the regulation of GCC activity, may be a possible site for the binding of Mg-ATP to GCC.

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Nighorn, A., P. J. Simpson, and D. B. Morton. "The novel guanylyl cyclase MsGC-I is strongly expressed in higher-order neuropils in the brain of Manduca sexta." Journal of Experimental Biology 204, no. 2 (January 15, 2001): 305–14. http://dx.doi.org/10.1242/jeb.204.2.305.

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Guanylyl cyclases are usually characterized as being either soluble (sGCs) or receptor (rGCs). We have recently cloned a novel guanylyl cyclase, MsGC-I, from the developing nervous system of the hawkmoth Manduca sexta that cannot be classified as either an sGC or an rGC. MsGC-I shows highest sequence identity with receptor guanylyl cyclases throughout its catalytic and dimerization domains, but does not contain the ligand-binding, transmembrane or kinase-like domains characteristic of receptor guanylyl cyclases. In addition, MsGC-I contains a C-terminal extension of 149 amino acid residues. In this paper, we report the expression of MsGC-I in the adult. Northern blots show that it is expressed preferentially in the nervous system, with high levels in the pharate adult brain and antennae. In the antennae, immunohistochemical analyses show that it is expressed in the cell bodies and dendrites, but not axons, of olfactory receptor neurons. In the brain, it is expressed in a variety of sensory neuropils including the antennal and optic lobes. It is also expressed in structures involved in higher-order processing including the mushroom bodies and central complex. This complicated expression pattern suggests that this novel guanylyl cyclase plays an important role in mediating cyclic GMP levels in the nervous system of Manduca sexta.

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Callahan, W., M. Forster, and T. Toop. "Evidence of a guanylyl cyclase natriuretic peptide receptor in the gills of the new zealand hagfish Eptatretus cirrhatus (Class Agnatha)." Journal of Experimental Biology 203, no. 17 (September 1, 2000): 2519–28. http://dx.doi.org/10.1242/jeb.203.17.2519.

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Natriuretic peptide binding sites were examined in the gills of the hagfish Eptatretus cirrhatus (Class Agnatha, subfamily Eptatretinae) using radio-ligand binding techniques, molecular cloning and guanylyl cyclase assays. Iodinated rat atrial natriuretic peptide ((125)I-rANP) and iodinated porcine C-type natriuretic peptide ((125)I-pCNP) bound specifically to the lamellar folds and cavernous tissue of E. cirrhatus gills, and 0.3 nmol l(−1) rat ANP competed for 50 % of specific (125)I-rANP binding sites. Affinity cross-linking of (125)I-rANP to gill membranes followed by sodium dodecylsulphate-polyacrylamide gel electrophoresis revealed a single binding site of 150 kDa. In the presence of Mn(2+), 0.1 nmol l(−1) rANP inhibited cGMP production, whereas 1 micromol l(−1) rANP stimulated cGMP production rates. At 1 micromol l(−1), pCNP also stimulated cGMP production. The production of cGMP was also measured in the presence and absence of ATP with either Mn(2+) or Mg(2+). Reverse transcriptase polymerase chain reaction (RT-PCR) of hagfish gill RNA, followed by cloning and sequencing of PCR products, produced a partial cDNA sequence of a natriuretic peptide guanylyl cyclase receptor. The deduced amino acid sequence indicated 87–91 % homology with other natriuretic peptide guanylyl cyclase receptors. This study indicates the presence of a natriuretic peptide guanylyl cyclase receptor in the gills of E. cirrhatus that is similar to the natriuretic peptide guanylyl cyclase receptors in higher vertebrates. These observations demonstrate that the coupling of natriuretic peptide receptors with guanylyl cyclase has a long evolutionary history.

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Guo, Lai-Jing, Abdel A. Alli, Douglas C. Eaton, and Hui-Fang Bao. "ENaC is regulated by natriuretic peptide receptor-dependent cGMP signaling." American Journal of Physiology-Renal Physiology 304, no. 7 (April 1, 2013): F930—F937. http://dx.doi.org/10.1152/ajprenal.00638.2012.

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Epithelial sodium channels (ENaCs) located at the apical membrane of polarized epithelial cells are regulated by the second messenger guanosine 3′,5′-cyclic monophosphate (cGMP). The mechanism for this regulation has not been completely characterized. Guanylyl cyclases synthesize cGMP in response to various intracellular and extracellular signals. We investigated the regulation of ENaC activity by natriuretic peptide-dependent activation of guanylyl cyclases in Xenopus 2F3 cells. Confocal microscopy studies show natriuretic peptide receptors (NPRs), including those coupled to guanylyl cyclases, are expressed at the apical membrane of 2F3 cells. Single-channel patch-clamp studies using 2F3 cells revealed that atrial natriuretic peptide (ANP) or 8-(4-chlorophenylthio)-cGMP, but not C-type natriuretic peptide or cANP, decreased the open probability of ENaC. This suggests that NPR-A, but not NPR-B or NPR-C, is involved in the natriuretic peptide-mediated regulation of ENaC activity. Also, it is likely that a signaling pathway involving cGMP and nitric oxide (NO) are involved in this mechanism, since inhibitors of soluble guanylyl cyclase, protein kinase G, inducible NO synthase, or an NO scavenger blocked or reduced the effect of ANP on ENaC activity.

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Mukaddam-Daher, S., J. Tremblay, N. Fujio, C. Koch, M. Jankowski, E. W. Quillen, and J. Gutkowska. "Alteration of lung atrial natriuretic peptide receptors in genetic cardiomyopathy." American Journal of Physiology-Lung Cellular and Molecular Physiology 271, no. 1 (July 1, 1996): L38—L45. http://dx.doi.org/10.1152/ajplung.1996.271.1.l38.

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These studies were designed to characterize the atrial natriuretic peptide (ANF) receptor subtypes [guanylyl cyclase natriuretic peptide receptors (NPR-A, NPR-B) and NPR-C] in lungs of normal hamsters and to evaluate alterations in receptor kinetics in genetic cardiomyopathy (CMO), a model of human congestive heart failure. Lung membranes were obtained from normal and CMO 200-to 230-day-old hamsters. Cross-linking and competitive binding receptor assays using 125I-labeled human ANF showed that lung membranes exhibit NPR, mainly guanylyl cyclase NPR-A and clearance NPR-C receptors. Stimulation of guanylyl cyclase by ANF and C-type natriuretic peptide (CNP) confirmed the presence of NPR-A and NPR-B. The maximum binding capacity of total ANF binding sites (442 +/- 68 vs. 271 +/- 57 fmol/mg protein, P < 0.05) was reduced, but dissociation constant (0.26 +/- 0.04 vs. 0.41 +/- 0.08 nM) was not altered in CMO animals. Similar reductions were observed in the binding sites for brain natriuretic peptide (BNP; 438 +/- 83 vs. 236 +/- 53 fmol/mg protein) and CNP (321 +/- 80 vs. 165 +/- 56 fmol/mg protein, P < 0.05) which may reflect a decline in NPR-A and NPR-B and/or NPR-C. Acid wash improved binding of 125I-labeled rat ANF to lung membranes of both normal and CMO hamsters, but the tendency towards reduced binding in CMO hamsters did not reach statistical significance, implying that downregulation may not have been due only to prior occupancy of the receptors. Transcripts of NPR-A, NPR-B, and NPR-C receptors in hamster lungs were detected by quantitative polymerase chain reaction. Compared with normal controls, the CMO hamster lung NPR-A mRNA was reduced by 50%, but NPR-B mRNA and NPR-C mRNA were not altered. Moreover, CMO hamster lungs showed less activation of guanylyl cyclase by ANF. These studies demonstrate that lung NPR are downregulated in hamster CMO.

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Bominaar, A. A., and P. J. Van Haastert. "Chemotactic antagonists of cAMP inhibit Dictyostelium phospholipase C." Journal of Cell Science 104, no. 1 (January 1, 1993): 181–85. http://dx.doi.org/10.1242/jcs.104.1.181.

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In Dictyostelium discoideum extracellular cAMP induces chemotaxis via a transmembrane signal transduction cascade consisting of surface cAMP receptors, G-proteins and effector enzymes including adenylyl cyclase, guanylyl cyclase and phospholipase C. Previously it was demonstrated that some cAMP derivatives such as 3′-deoxy-3′-aminoadenosine 3′:5′-monophosphate (3′NH-cAMP) bind to the receptor and induce normal activation of adenylyl cyclase and guanylyl cyclase. However these analogues do not induce chemotaxis, probably because the signal is transduced in an inappropriate manner. We have now studied the regulation of phospholipase C by cAMP and these chemotactic antagonists. cAMP induced the two-fold activation of phospholipase C leading to a transient increase of Ins(1,4,5)P3 levels. In contrast, the analogues induced a rapid decrease of intracellular Ins(1,4,5)P3 levels, due to the inhibition of phospholipase C activity. In a transformed cell-line lacking the G-protein that mediates phospholipase C inhibition, 3′NH-cAMP did not decrease phospholipase C activity and was no longer an antagonist of chemotaxis. These results suggest that inhibition of phospholipase C leads to aberrant chemotaxis.

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9

Carrithers, Stephen L., Cobern E. Ott, Michael J. Hill, Brett R. Johnson, Weiyan Cai, Jason J. Chang, Rajesh G. Shah, et al. "Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor." Kidney International 65, no. 1 (January 2004): 40–53. http://dx.doi.org/10.1111/j.1523-1755.2004.00375.x.

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10

Basu, Nirmalya, Najla Arshad, and Sandhya S. Visweswariah. "Receptor guanylyl cyclase C (GC-C): regulation and signal transduction." Molecular and Cellular Biochemistry 334, no. 1-2 (December 4, 2009): 67–80. http://dx.doi.org/10.1007/s11010-009-0324-x.

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11

Paulding, W. R., and C. Sumners. "Protein kinase C modulates natriuretic peptide receptors in astroglial cultures from rat brain." American Journal of Physiology-Cell Physiology 270, no. 3 (March 1, 1996): C740—C747. http://dx.doi.org/10.1152/ajpcell.1996.270.3.c740.

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We determined previously that astroglia cultured from newborn rat brain contain both guanylyl cyclase-coupled and atrial natriuretic peptide (ANP)-C natriuretic peptide receptors. Here, we investigated the effects of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) on these receptor subtypes in cultured astroglia to understand the intracellular processes involved in the modulation of natriuretic peptide receptors in these cells. PMA (10 nM to 1 microM; 15 min to 24 h) treatment elicited a time- and concentration-dependent decrease in the numbers of 125I-labeled ANP specific binding sites, which was inhibited by the PKC antagonist staurosporine (500 nM). Furthermore, PMA (100 nM, 2 or 24 h) treatment elicited a significant decrease in the specific binding of 125I-des-Cys-Cys-ANP, an ANP-C receptor selective ligand. PMA (10 nM to 1 microM; 30 min) treatment also significantly decreased ANP (100 nM)-stimulated guanosine 3', 5'-cyclic monophosphate levels in cultured astroglia, an effect unmodified by phosphodiesterase inhibition. These data indicate that PKC modulates both guanylyl cyclase-coupled and ANP-C natriuretic peptide receptors in cultured astroglia.

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Schulz, Stephanie. "C-type natriuretic peptide and guanylyl cyclase B receptor." Peptides 26, no. 6 (June 2005): 1024–34. http://dx.doi.org/10.1016/j.peptides.2004.08.027.

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13

Bhandari, Rashna, Roy Mathew, K. Vijayachandra, and Sandhya S. Visweswariah. "Tyrosine phosphorylation of the human guanylyl cyclase C receptor." Journal of Biosciences 25, no. 4 (December 2000): 339–46. http://dx.doi.org/10.1007/bf02703787.

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Edmund, Aaron B., Timothy F. Walseth, Nicholas M. Levinson, and Lincoln R. Potter. "The pseudokinase domains of guanylyl cyclase–A and –B allosterically increase the affinity of their catalytic domains for substrate." Science Signaling 12, no. 566 (January 29, 2019): eaau5378. http://dx.doi.org/10.1126/scisignal.aau5378.

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Natriuretic peptides regulate multiple physiologic systems by activating transmembrane receptors containing intracellular guanylyl cyclase domains, such as GC-A and GC-B, also known as Npr1 and Npr2, respectively. Both enzymes contain an intracellular, phosphorylated pseudokinase domain (PKD) critical for activation of the C-terminal cGMP-synthesizing guanylyl cyclase domain. Because ATP allosterically activates GC-A and GC-B, we investigated how ATP binding to the PKD influenced guanylyl cyclase activity. Molecular modeling indicated that all the residues of the ATP-binding site of the prototypical kinase PKA, except the catalytic aspartate, are conserved in the PKDs of GC-A and GC-B. Kinase-inactivating alanine substitutions for the invariant lysine in subdomain II or the aspartate in the DYG-loop of GC-A and GC-B failed to decrease enzyme phosphate content, consistent with the PKDs lacking kinase activity. In contrast, both mutations reduced enzyme activation by blocking the ability of ATP to decrease the Michaelis constant without affecting peptide-dependent activation. The analogous lysine-to-alanine substitution in a glutamate-substituted phosphomimetic mutant form of GC-B also reduced enzyme activity, consistent with ATP stimulating guanylyl cyclase activity through an allosteric, phosphorylation-independent mechanism. Mutations designed to rigidify the conserved regulatory or catalytic spines within the PKDs increased guanylyl cyclase activity, increased sensitivity to natriuretic peptide, or reduced the Michaelis constant in the absence of ATP, consistent with ATP binding stabilizing the PKD in a conformation analogous to that of catalytically active kinases. We conclude that allosteric mechanisms evolutionarily conserved in the PKDs promote the catalytic activation of transmembrane guanylyl cyclases.

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Gunning, Mark, Richard J. Solomon, Franklin H. Epstein, and Patricio Silva. "Role of guanylyl cyclase receptors for CNP in salt secretion by shark rectal gland." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 273, no. 4 (October 1, 1997): R1400—R1406. http://dx.doi.org/10.1152/ajpregu.1997.273.4.r1400.

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The role of C-type natriuretic peptide (CNP) and its guanylyl cyclase-linked receptors in mediating salt secretion by the rectal gland of the spiny dogfish shark ( Squalus acanthias) was investigated using HS-142–1, a competitive inhibitor of the binding of natriuretic peptides to their guanylyl cyclase receptors. CNP binds to receptors and activates guanylyl cyclase in rectal gland membranes in a way that is inhibited by HS-142–1. Guanylyl cyclase activation in rectal gland membranes is far more sensitive to CNP than to atrial natriuretic peptide, whereas the reverse is true for membranes derived from mammalian (rabbit) renal collecting duct cells. HS-142–1 inhibited the stimulatory effect of CNP on ouabain-inhibitable oxygen consumption by rectal gland tubules. In explanted rectal glands continuously perfused with blood from intact donor sharks, HS-142–1 inhibited the increase in salt secretion normally provoked by infusing isotonic saline solutions into the donor animal. These results strongly support the view that CNP released into the systemic circulation in response to volume expansion mediates the secretion of chloride by the rectal gland via receptors linked to guanylyl cyclase.

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Carrithers, S. L., B. Taylor, W. Y. Cai, B. R. Johnson, C. E. Ott, R. N. Greenberg, and B. A. Jackson. "Guanylyl cyclase-C receptor mRNA distribution along the rat nephron." Regulatory Peptides 95, no. 1-3 (November 2000): 65–74. http://dx.doi.org/10.1016/s0167-0115(00)00139-7.

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17

Kuhn, Michaela. "Molecular Physiology of Membrane Guanylyl Cyclase Receptors." Physiological Reviews 96, no. 2 (April 2016): 751–804. http://dx.doi.org/10.1152/physrev.00022.2015.

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cGMP controls many cellular functions ranging from growth, viability, and differentiation to contractility, secretion, and ion transport. The mammalian genome encodes seven transmembrane guanylyl cyclases (GCs), GC-A to GC-G, which mainly modulate submembrane cGMP microdomains. These GCs share a unique topology comprising an extracellular domain, a short transmembrane region, and an intracellular COOH-terminal catalytic (cGMP synthesizing) region. GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure/volume and energy balance. GC-B is activated by C-type natriuretic peptide, stimulating endochondral ossification in autocrine way. GC-C mediates the paracrine effects of guanylins on intestinal ion transport and epithelial turnover. GC-E and GC-F are expressed in photoreceptor cells of the retina, and their activation by intracellular Ca2+-regulated proteins is essential for vision. Finally, in the rodent system two olfactorial GCs, GC-D and GC-G, are activated by low concentrations of CO2and by peptidergic (guanylins) and nonpeptidergic odorants as well as by coolness, which has implications for social behaviors. In the past years advances in human and mouse genetics as well as the development of sensitive biosensors monitoring the spatiotemporal dynamics of cGMP in living cells have provided novel relevant information about this receptor family. This increased our understanding of the mechanisms of signal transduction, regulation, and (dys)function of the membrane GCs, clarified their relevance for genetic and acquired diseases and, importantly, has revealed novel targets for therapies. The present review aims to illustrate these different features of membrane GCs and the main open questions in this field.

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Nandi, Animesh, Sandhya S. Visweswariah, K. Suguna, and Avadhesha Surolia. "Topological mimicry and epitope duplication in the guanylyl cyclase C receptor." Protein Science 7, no. 10 (October 1998): 2175–83. http://dx.doi.org/10.1002/pro.5560071015.

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Nandi, Animesh, Rashna Bhandari, and Sandhya S. Visweswariah. "Epitope conservation and immunohistochemical localization of the guanylin/stable toxin peptide receptor, guanylyl cyclase C." Journal of Cellular Biochemistry 66, no. 4 (September 15, 1997): 500–511. http://dx.doi.org/10.1002/(sici)1097-4644(19970915)66:4<500::aid-jcb9>3.0.co;2-p.

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20

Basu, Nirmalya, Rashna Bhandari, Vivek T. Natarajan, and Sandhya S. Visweswariah. "Cross Talk between Receptor Guanylyl Cyclase C and c-src Tyrosine Kinase Regulates Colon Cancer Cell Cytostasis." Molecular and Cellular Biology 29, no. 19 (July 20, 2009): 5277–89. http://dx.doi.org/10.1128/mcb.00001-09.

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ABSTRACT Increased activation of c-src seen in colorectal cancer is an indicator of a poor clinical prognosis, suggesting that identification of downstream effectors of c-src may lead to new avenues of therapy. Guanylyl cyclase C (GC-C) is a receptor for the gastrointestinal hormones guanylin and uroguanylin and the bacterial heat-stable enterotoxin. Though activation of GC-C by its ligands elevates intracellular cyclic GMP (cGMP) levels and inhibits cell proliferation, its persistent expression in colorectal carcinomas and occult metastases makes it a marker for malignancy. We show here that GC-C is a substrate for inhibitory phosphorylation by c-src, resulting in reduced ligand-mediated cGMP production. Consequently, active c-src in colonic cells can overcome GC-C-mediated control of the cell cycle. Furthermore, docking of the c-src SH2 domain to phosphorylated GC-C results in colocalization and further activation of c-src. We therefore propose a novel feed-forward mechanism of activation of c-src that is induced by cross talk between a receptor GC and a tyrosine kinase. Our findings have important implications in understanding the molecular mechanisms involved in the progression and treatment of colorectal cancer.

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Scheving, L. A., and K. M. Chong. "Differential processing of guanylyl cyclase C along villus-crypt axis of rat small intestine." American Journal of Physiology-Cell Physiology 272, no. 6 (June 1, 1997): C1995—C2004. http://dx.doi.org/10.1152/ajpcell.1997.272.6.c1995.

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Many strains of enterotoxigenic Escherichia coli produce a heat-stable peptide enterotoxin (STa) that binds to the intestinal receptor guanylyl cyclase C (GC-C). STa receptors are structurally heterogeneous, but the molecular events causing this heterogeneity remain obscure. We examined the influence of cell position along the villus-crypt axis on STa receptor heterogeneity by fractionating EDTA-dissociated cells that detached in a villus-to-crypt direction. STa affinity labeling experiments revealed that the initially released villus “tip” fraction had four major STa binding proteins (STBPs), with relative molecular weight (M(r)) of 150,000, 135,000, 125,000, and 95,000, that did not react with a GC-C carboxy-terminal antibody. Yet succeeding villus cell fractions had major immunoreactive STBPs with M(r) of 275,000 and 250,000. Limited proteolysis of these larger GC-C isoforms produced 1) smaller STBPs that had M(r) similar to those in the initial villus fraction, 2) a 65,000 M(r) protein GC-C isoform that did not bind STa, and 3) elevated basal and STa-induced cyclase activity. Our data show that STBP structural heterogeneity in the intact intestine arises largely from multisite proteolytic processing of GC-C.

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Hirose, Masamichi, Yasuyuki Furukawa, Yusuke Miyashita, Fumio Kurogouchi, Koichi Nakajima, Masato Tsuboi, and Shigetoshi Chiba. "CNP causes receptor-mediated positive dromotropic effects in anesthetized dog hearts." American Journal of Physiology-Heart and Circulatory Physiology 275, no. 2 (August 1, 1998): H717—H720. http://dx.doi.org/10.1152/ajpheart.1998.275.2.h717.

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No data are available for the direct effect of C-type natriuretic peptide (CNP) on atrioventricular (AV) conduction in mammalian hearts. Thus we studied the dromotropic effects of CNP-22 injected into the AV node artery in autonomically decentralized hearts in open-chest, anesthetized dogs. CNP decreased AV interval (AV conduction time) in a dose-dependent manner with increase in coronary artery blood flow rate in six anesthetized dogs. Isosorbide dinitrate did not affect AV interval, but it increased coronary artery blood flow rate. A guanylyl cyclase-linked natriuretic peptide receptor antagonist, HS-142–1, inhibited the decreases in AV interval and the increases in coronary blood flow rate in response to CNP, whereas propranolol did not affect the positive dromotropic response to CNP. These results demonstrate that CNP decreases AV interval and increases coronary artery blood flow rate mediated by a guanylyl cyclase-linked natriuretic peptide receptor, but not β-adrenoceptor, in the dog heart.

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Fonteles, Manasses C., Stephen L. Carrithers, Helena S. A. Monteiro, Andre F. Carvalho, Gustavo R. Coelho, Richard N. Greenberg, and Leonard R. Forte. "Renal effects of serine-7 analog of lymphoguanylin in ex vivo rat kidney." American Journal of Physiology-Renal Physiology 280, no. 2 (February 1, 2001): F207—F213. http://dx.doi.org/10.1152/ajprenal.2001.280.2.f207.

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Guanylin and uroguanylin compose a family of natriuretic, diuretic, and kaliuretic peptides that bind to and activate apical membrane receptor guanylyl cyclase signaling molecules in renal and intestinal epithelia. Recently, a complementary DNA encoding an additional member of the guanylin family of cGMP-regulating peptides was isolated from lymphoid tissues of the opossum and was termed lymphoguanylin (LGN). A peptide analog of opossum LGN was synthesized containing a single disulfide bond with the internal cysteine-7 replaced by a serine residue (LGNCys7→Ser7). The biological activity of LGNSer was tested by using a cGMP bioassay with cultured T84 (human intestinal) cells and opossum kidney (OK) cells. LGNSer has potencies and efficacies for activation of cGMP production in the intestinal and kidney cell lines that are 100- and 1,000-fold higher than LGN, respectively. In the isolated perfused rat kidney, LGNSer stimulated a maximal increase in fractional Na+ excretion from 24.8 ± 3.0 to 36.3 ± 3.3% 60 min after administration and enhanced urine flow from 0.15 ± 0.01 to 0.24 ± 0.01 ml · g−1 · min−1. LGNSer (0.69 μM) also increased fractional K+excretion from 27.3 ± 2.3 to 38.0 ± 3.0% and fractional Cl− excretion from 26.1 ± 0.8 to 43.5 ± 1.9. A ninefold increase in the urinary excretion of cGMP from 1.00 ± 0.04 to 9.28 ± 1.14 pmol/ml was elicited by LGNSer, whereas cAMP levels were not changed on peptide administration. These findings demonstrate that LGNSer, which contains a single disulfide bond like native LGN, activates guanylyl cyclase-C (GC-C) receptors in T84 and OK cells and may be very helpful in studying the physiological importance of activation of GC-C in vivo. LGNSer also exhibits full activity in the isolated perfused kidney equivalent to that observed previously with opossum uroguanylin, suggesting a physiological role for LGN in renal function. Thus the single amino acid substitution enhances the activity and potency of LGN.

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Ritter, D., A. D. Dean, Z. H. Guan, and J. E. Greenwald. "Polarized distribution of renal natriuretic peptide receptors in normal physiology and ischemia." American Journal of Physiology-Renal Physiology 269, no. 6 (December 1, 1995): F918—F925. http://dx.doi.org/10.1152/ajprenal.1995.269.6.f918.

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The polarized expression of guanylyl cyclase-coupled natriuretic peptide receptors, types A (GC-A) and B (GC-B), was measured in inner medullary collecting ducts (IMCD) of normal and ischemic rat kidneys, as well as in IMCD cells. Exposure of normal rat kidney medulla to an anti-GC-A antibody demonstrated a propensity of receptor staining on the cellular basal membrane. The polarization of GC-A receptors was lost in the ischemic kidney. The maximal binding capacity of 125I-atrial natriuretic factor (ANF) to the basal membrane of the inner medullary cell line mIMCD-K2 was five times greater than that to the apical membrane. ANF or C-type natriuretic peptide (CNP) added to the basal side of cultured cells resulted in guanosine 3',5'-cyclic monophosphate formation that was greater than when applied to the apical side. Depletion of ATP stores in cultured cells was followed by an increase of 125I-ANF binding to apical cellular membranes. Similar results were obtained when receptor guanylyl cyclase activity was assayed. In conclusion, these results suggest that functional GC-A and GC-B receptors are present predominantly on the basal membrane of IMCD. However, depletion of cellular ATP stores such as in ischemia is followed by a partial loss of polarization.

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Kämpf, U., M. Kruhøffer, G. Bargsten, D. Grube, W. G. Forssmann, and Y. Cetin. "Guanylin and its receptor (guanylyl cyclase C): expression and cell specific localization in the gastrointestinal tract." Regulatory Peptides 64, no. 1-3 (July 1996): 85. http://dx.doi.org/10.1016/0167-0115(96)87890-6.

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Abbey, Sarah E., and Lincoln R. Potter. "Lysophosphatidic Acid Inhibits C-Type Natriuretic Peptide Activation of Guanylyl Cyclase-B." Endocrinology 144, no. 1 (January 1, 2003): 240–46. http://dx.doi.org/10.1210/en.2002-220702.

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Abstract C-type natriuretic peptide (CNP), found in endothelial cells, chondrocytes, and neurons, binds its cognate transmembrane receptor, natriuretic peptide receptor-B (NPR-B/GC-B), and stimulates the synthesis of the intracellular signaling molecule, cGMP. The known physiologic consequences of this binding event are vasorelaxation, inhibition of cell proliferation, and the stimulation of long bone growth. Here we report that 10% fetal bovine serum markedly reduced CNP-dependent cGMP elevations in NIH3T3 fibroblast. The purified serum components platelet-derived growth factor and lysophosphatidic acid (LPA) mimicked the effect of serum on CNP-dependent cGMP elevations, but the latter factor resulted in the most dramatic reductions. The LPA-dependent inhibition was rapid and dose dependent, having t1/2 and IC50 values of approximately 5 min and 3.0 μm LPA, respectively. The decreased cGMP concentrations resulted from reduced CNP-dependent NPR-B guanylyl cyclase activity that did not require losses in receptor protein or activation of protein kinase C, indicating a previously undescribed desensitization pathway. These data suggest that NPR-B is repressed by LPA and that one mechanism by which LPA exerts its effects is through the heterologous desensitization of the CNP/NPR-B/cGMP pathway. We hypothesize that cross-talk between the LPA and CNP signaling pathway maximizes the response of fibroblasts in the wound-healing process.

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Rose, R. A., A. E. Lomax, and W. R. Giles. "Inhibition of L-type Ca2+ current by C-type natriuretic peptide in bullfrog atrial myocytes: an NPR-C-mediated effect." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 6 (December 2003): H2454—H2462. http://dx.doi.org/10.1152/ajpheart.00388.2003.

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Single atrial myocytes were isolated from the bullfrog heart and studied under current and voltage clamp conditions to determine the electrophysiological effects of the C-type natriuretic peptide (CNP). CNP (10–8 M) significantly shortened the action potential and reduced its peak amplitude after the application of isoproteronol (10–7 M). In voltage clamp studies, CNP inhibited isoproteronol-stimulated L-type Ca2+ current ( ICa) without any significant effect on the inward rectifier K+ current. The effects of cANF (10–8 M), a selective agonist of the natriuretic peptide C receptor (NPR-C), were very similar to those of CNP. Moreover, HS-142-1, an antagonist of the guanylyl cyclase-linked NPR-A and NPR-B receptors did not alter the inhibitory effect of CNP on ICa. Inclusion of cAMP in the recording pipette to stimulate ICa at a point downstream from adenylyl cyclase increased ICa, but this effect was not inhibited by cANF. These results provide the first demonstration that CNP can inhibit ICa after binding to NPR-C, and suggest that this inhibition involves a decrease in adenylyl cyclase activity, which leads to reduced intracellular levels of cAMP.

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Kuwayama, H., S. Ishida, and P. J. Van Haastert. "Non-chemotactic Dictyostelium discoideum mutants with altered cGMP signal transduction." Journal of Cell Biology 123, no. 6 (December 15, 1993): 1453–62. http://dx.doi.org/10.1083/jcb.123.6.1453.

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Folic acid and cAMP are chemoattractants in Dictyostelium discoideum, which bind to different surface receptors. The signal is transduced from the receptors via different G proteins into a common pathway which includes guanylyl cyclase and acto-myosin. To investigate this common pathway, ten mutants which do not react chemotactically to both cAMP and folic acid were isolated with a simple new chemotactic assay. Genetic analysis shows that one of these mutants (KI-10) was dominant; the other nine mutants were recessive, and comprise nine complementation groups. In wild-type cells, the chemoattractants activate adenylyl cyclase, phospholipase C, and guanylyl cyclase in a transient manner. In mutant cells the formation of cAMP and IP3 were generally normal, whereas the cGMP response was altered in most of the ten mutants. Particularly, mutant KI-8 has strongly reduced basal guanylyl cyclase activity; the enzyme is present in mutant KI-10, but can not be activated by cAMP or folic acid. The cGMP response of five other mutants is altered in either magnitude, dose dependency, or kinetics. These observations suggest that the second messenger cGMP plays a key role in chemotaxis in Dictyostelium.

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Yuen, I. S., R. Jain, J. D. Bishop, D. F. Lindsey, W. J. Deery, P. J. Van Haastert, and R. H. Gomer. "A density-sensing factor regulates signal transduction in Dictyostelium." Journal of Cell Biology 129, no. 5 (June 1, 1995): 1251–62. http://dx.doi.org/10.1083/jcb.129.5.1251.

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Dictyostelium discoideum initiates development when cells overgrow their bacterial food source and starve. To coordinate development, the cells monitor the extracellular level of a protein, conditioned medium factor (CMF), secreted by starved cells. When a majority of the cells in a given area have starved, as signaled by CMF secretion, the extracellular level of CMF rises above a threshold value and permits aggregation of the starved cells. The cells aggregate using relayed pulses of cAMP as the chemoattractant. Cells in which CMF accumulation has been blocked by antisense do not aggregate except in the presence of exogenous CMF. We find that these cells are viable but do not chemotax towards cAMP. Videomicroscopy indicates that the inability of CMF antisense cells to chemotax is not due to a gross defect in motility, although both video and scanning electron microscopy indicate that CMF increases the frequency of pseudopod formation. The activations of Ca2+ influx, adenylyl cyclase, and guanylyl cyclase in response to a pulse of cAMP are strongly inhibited in cells lacking CMF, but are rescued by as little as 10 s exposure of cells to CMF. The activation of phospholipase C by cAMP is not affected by CMF. Northern blots indicate normal levels of the cAMP receptor mRNA in CMF antisense cells during development, while cAMP binding assays and Scatchard plots indicate that CMF antisense cells contain normal levels of the cAMP receptor. In Dictyostelium, both adenylyl and guanylyl cyclases are activated via G proteins. We find that the interaction of the cAMP receptor with G proteins in vitro is not measurably affected by CMF, whereas the activation of adenylyl cyclase by G proteins requires cells to have been exposed to CMF. CMF thus appears to regulate aggregation by regulating an early step of cAMP signal transduction.

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Rotem, Ronit, Nadav Zamir, Nurit Keynan, Dalit Barkan, Haim Breitbart, and Zvi Naor. "Atrial natriuretic peptide induces acrosomal exocytosis of human spermatozoa." American Journal of Physiology-Endocrinology and Metabolism 274, no. 2 (February 1, 1998): E218—E223. http://dx.doi.org/10.1152/ajpendo.1998.274.2.e218.

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Acrosomal exocytosis in mammalian spermatozoa is a process essential for fertilization. We report here that atrial natriuretic peptide (ANP) markedly stimulates acrosomal exocytosis of capacitated human spermatozoa. Typically, ANP exerts some of its actions via activation of the ANP receptor (ANPR-A), a particulate guanylyl cyclase-linked receptor, and subsequent formation of guanosine 3′,5′-cyclic monophosphate (cGMP). We found that ANP-stimulated acrosome reaction was inhibited by the competitive ANPR-A antagonist anantin, indicating a receptor-mediated process. A linear fragment of ANP, ANP-(13—28), and another ANP-like compound, brain natriuretic peptide, were inactive. The stimulatory effect of ANP on acrosome reaction was mimicked by the permeable cGMP analog, 8-bromo-cGMP (8-BrcGMP). Addition of the protein kinase C (PKC) inhibitors, staurosporine and GF-109203X, resulted in a dose-related inhibition of ANP-induced acrosome reaction. Also, downregulation of endogeneous PKC activity resulted in inhibition of ANP- but not 8-BrcGMP-induced acrosome reaction. Removal of extracellular Ca2+ abolished ANP-induced acrosome reaction. Thus ANP via Ca2+ influx, PKC activation, and stimulation of particulate guanylyl cyclase may play a role in the induction of acrosome reaction of human spermatozoa.

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Sangaralingham, S. Jeson, and John C. Burnett. "Relaxing With C-Type Natriuretic Peptide, the Guanylyl Cyclase B Receptor, and Pericytes." Circulation 138, no. 5 (July 31, 2018): 509–12. http://dx.doi.org/10.1161/circulationaha.118.035132.

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Bose, Avipsa, Sanghita Banerjee, and Sandhya S. Visweswariah. "Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease‐related mutations." IUBMB Life 72, no. 6 (April 15, 2020): 1145–59. http://dx.doi.org/10.1002/iub.2283.

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Scheving, L. A., W. E. Russell, and K. M. Chong. "Structure, glycosylation, and localization of rat intestinal guanylyl cyclase C: modulation by fasting." American Journal of Physiology-Gastrointestinal and Liver Physiology 271, no. 6 (December 1, 1996): G959—G968. http://dx.doi.org/10.1152/ajpgi.1996.271.6.g959.

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Guanylyl cyclase C (GC-C), an intestinal receptor guanylyl cyclase, binds diarrhea-producing bacterial ligands such as the Escherichia coli heat stable enterotoxin. We examined the regulatory influence of feeding and fasting on the expression, structure, and biochemical properties of GC-C. When solubilized at 4 degrees C under nonreducing conditions, GC-C from both fed and fasted rats migrated on 7% sodium dodecyl sulfate-polyacrylamide electrophoretic gels as two extremely large aggregates that barely penetrated the stacking and resolving gels. Chemical reduction of disulfide linkages disaggregated GC-C in fed but not fasted rat samples, causing it to migrate as smaller forms (approximately 220 and 240 kDa). Although GC-C aggregates from fasted rats resisted this disaggregating effect of chemical reduction, they rapidly acquired it within 90 min of refeeding. When solubilized at denaturing temperatures (95 degrees C) under reducing conditions, GC-C aggregates largely disassembled into four smaller proteins (relative molecular weight approximately 140,000, 131,000, 85,000, and 65,000). However, the 131-kDa glycoprotein was disproportionately increased in fasted rat membranes. This unit and the 220-kDa unit were sensitive to endoglycosidase H. Subcellular fractionation and immunohistochemical studies revealed a major redistribution of GC-C from surface to intracellular enterocyte sites during fasting.

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Kake, Takei, Hidetomo Kitamura, Yuichiro Adachi, Tetsuro Yoshioka, Tomoyuki Watanabe, Hiroaki Matsushita, Toshihito Fujii, et al. "Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice." American Journal of Physiology-Endocrinology and Metabolism 297, no. 6 (December 2009): E1339—E1348. http://dx.doi.org/10.1152/ajpendo.00272.2009.

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C-type natriuretic peptide (CNP) plays a critical role in endochondral ossification through guanylyl cyclase-B (GC-B), a natriuretic peptide receptor subtype. Cartilage-specific overexpression of CNP enhances skeletal growth and rescues the dwarfism in a transgenic achondroplasia model with constitutive active mutation of fibroblast growth factor receptor-3. For future clinical application, the efficacy of CNP administration on skeletal growth must be evaluated. Due to the high clearance of CNP, maintaining a high concentration is technically difficult. However, to model high blood CNP concentration, we established a liver-targeted CNP-overexpressing transgenic mouse (SAP-CNP tgm). SAP-CNP tgm exhibited skeletal overgrowth in proportion to the blood CNP concentration and revealed phenotypes of systemic stimulation of cartilage bones, including limbs, paws, costal bones, spine, and skull. Furthermore, in SAP-CNP tgm, the size of the foramen magnum, the insufficient formation of which results in cervico-medullary compression in achondroplasia, also showed significant increase. CNP primarily activates GC-B, but under high concentrations it cross-reacts with guanylyl cyclase-A (GC-A), a natriuretic peptide receptor subtype of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP). Although activation of GC-A could alter cardiovascular homeostasis, leading to hypotension and heart weight reduction, the skeletal overgrowth phenotype in the line of SAP-CNP tgm with mild overexpression of CNP did not accompany decrease of systolic blood pressure or heart weight. These results suggest that CNP administration stimulates skeletal growth without adverse cardiovascular effect, and thus CNP could be a promising remedy targeting achondroplasia.

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Wennberg, Paul W., Virginia M. Miller, Ton Rabelink, and John C. Burnett. "Further attenuation of endothelium-dependent relaxation imparted by natriuretic peptide receptor antagonism." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 4 (October 1, 1999): H1618—H1621. http://dx.doi.org/10.1152/ajpheart.1999.277.4.h1618.

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Nitric oxide (NO) is an important endothelium-derived relaxing factor that functions via activation of soluble guanylyl cyclase and cGMP generation in vascular smooth muscle. Recently, studies have described the synthesis and secretion of C-type natriuretic peptide (CNP) from endothelial cells. This peptide also mediates relaxation via cGMP but through activation of particulate guanylyl cyclase. We tested the hypothesis that endothelium-dependent relaxations to acetylcholine or bradykinin in isolated canine coronary arteries involve both releases of NO and CNP. Rings of canine coronary arteries were incubated with either inhibitors of NO production ( N G-monomethyl-l-arginine,l-NMMA) or the natriuretic peptide receptor antagonist HS-142-1. CNP caused concentration-dependent relaxations of rings with and without endothelium. These relaxations were attenuated by HS-142-1. Relaxations to acetylcholine and bradykinin were attenuated byl-NMMA alone but not attenuated by HS-142-1 alone. Coinhibition withl-NMMA and HS-142-1 significantly inhibited acetylcholine- and bradykinin-induced relaxation to a magnitude greater than either inhibitor alone. In summary, a novel interaction between the NO and the natriuretic peptide system is demonstrated by increased attenuation of endothelium-dependent relaxations to acetylcholine and bradykinin when both NO synthase and natriuretic peptide receptors are inhibited. These investigations support the concept of release of multiple endothelium-derived factors in response to acetylcholine- and bradykinin-receptor stimulation in endothelial cells, which may include CNP, as well as NO.

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Charney, Alan N., Richard W. Egnor, Jesline T. Alexander-Chacko, Valentin Zaharia, Elizabeth A. Mann, and Ralph A. Giannella. "Effect ofE. coliheat-stable enterotoxin on colonic transport in guanylyl cyclase C receptor-deficient mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 2 (February 1, 2001): G216—G221. http://dx.doi.org/10.1152/ajpgi.2001.280.2.g216.

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We studied the functional importance of the colonic guanylyl cyclase C (GCC) receptor in GCC receptor-deficient mice. Mice were anesthetized with pentobarbital sodium, and colon segments were studied in Ussing chambers in HCO3−Ringer under short-circuit conditions. Receptor-deficient mouse proximal colon exhibited similar net Na+absorption, lower net Cl−absorption, and a negative residual ion flux ( JR), indicating net HCO3−absorption compared with that in normal mice. In normal mouse proximal colon, mucosal addition of 50 nM Escherichia coli heat-stable enterotoxin (STa) increased the serosal-to-mucosal flux of Cl−( Js→mCl) and decreased net Cl−flux ( JnetCl) accompanied by increases in short-circuit current ( Isc), potential difference (PD), and tissue conductance ( G). Serosal STa had no effect. In distal colon neither mucosal nor serosal STa affected ion transport. In receptor-deficient mice, neither mucosal nor serosal 500 nM STa affected electrolyte transport in proximal or distal colon. In these mice, 1 mM 8-bromo-cGMP produced changes in proximal colon Js→mCland JnetCl, Isc, PD, G, and JRsimilar to mucosal STa addition in normal mice. We conclude that the GCC receptor is necessary in the mouse proximal colon for a secretory response to mucosal STa.

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Nakagawa, Hitoshi, and Yoshihiko Saito. "Roles of Natriuretic Peptides and the Significance of Neprilysin in Cardiovascular Diseases." Biology 11, no. 7 (July 6, 2022): 1017. http://dx.doi.org/10.3390/biology11071017.

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Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the guanylyl cyclase A receptor (GC-A), which synthesizes the second messenger cGMP in a wide variety of tissues and cells. C-type natriuretic peptide (CNP) activates the cGMP-producing guanylyl cyclase B receptor (GC-B) in chondrocytes, endothelial cells, and possibly smooth muscle cells, cardiomyocytes, and cardiac fibroblasts. The development of genetically modified mice has helped elucidate the physiological roles of natriuretic peptides via GC-A or GC-B. These include the hormonal effects of ANP/BNP in the vasculature, autocrine effects of ANP/BNP in cardiomyocytes, and paracrine effects of CNP in the vasculature and cardiomyocytes. Neprilysin (NEP) is a transmembrane neutral endopeptidase that degrades the three natriuretic peptides. Recently, mice overexpressing NEP, specifically in cardiomyocytes, revealed that local cardiac NEP plays a vital role in regulating natriuretic peptides in the heart tissue. Since NEP inhibition is a clinically accepted approach for heart failure treatment, the physiological roles of natriuretic peptides have regained attention. This article focuses on the physiological roles of natriuretic peptides elucidated in mice with GC-A or GC-B deletion, the significance of NEP in natriuretic peptide metabolism, and the long-term effects of angiotensin receptor-neprilysin inhibitor (ARNI) on cardiovascular diseases.

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Akieda-Asai, Sayaka, Hao Ma, and Yukari Date. "Palmitic acid induces guanylin gene expression through the Toll-like receptor 4/nuclear factor-κB pathway in rat macrophages." American Journal of Physiology-Cell Physiology 317, no. 6 (December 1, 2019): C1239—C1246. http://dx.doi.org/10.1152/ajpcell.00081.2019.

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Recently, we showed that double-transgenic rats overexpressing guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), specifically in macrophages demonstrate an antiobesity phenotype and low-expression levels of proinflammatory cytokines in the mesenteric fat even when fed a high-fat diet. Here, we examined the levels and mechanism of Gn and GC-C transcription following saturated fatty acid and lipopolysaccharide (LPS), an activator of Toll-like receptor 4 (TLR4), exposure by using the NR8383 macrophage cell line. In addition, the levels of guanylin and cGMP were increased by addition of either palmitic acid or LPS. Next, we investigated the interaction of the gene transcription and nuclear factor-κB (NF-κB) by using an NF-κB inhibitor and chromatin immunoprecipitation assay. We showed that palmitic acid induced Gn gene expression via TLR4 and NF-κB. Moreover, we demonstrated that NF-κB binding to the Gn promoter was responsible for the induction of gene transcription by palmitic acid or LPS. Our results indicate that saturated fatty acids such as palmitic acid activate Gn gene expression via the NF-κB pathway, raising the possibility that the activated Gn-GC-C system may contribute to the inhibition of high-fat diet-induced proinflammatory cytokines in macrophages.

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Ben Aissa, Manel, Alycia F. Tipton, Zachariah Bertels, Ronak Gandhi, Laura S. Moye, Madeline Novack, Brian M. Bennett, et al. "Soluble guanylyl cyclase is a critical regulator of migraine-associated pain." Cephalalgia 38, no. 8 (October 12, 2017): 1471–84. http://dx.doi.org/10.1177/0333102417737778.

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Background Nitric oxide (NO) has been heavily implicated in migraine. Nitroglycerin is a prototypic NO-donor, and triggers migraine in humans. However, nitroglycerin also induces oxidative/nitrosative stress and is a source of peroxynitrite – factors previously linked with migraine etiology. Soluble guanylyl cyclase (sGC) is the high affinity NO receptor in the body, and the aim of this study was to identify the precise role of sGC in acute and chronic migraine. Methods We developed a novel brain-bioavailable sGC stimulator (VL-102), and tested its hyperalgesic properties in mice. We also determined the effect of VL-102 on c-fos and calcitonin gene related peptide (CGRP) immunoreactivity within the trigeminovascular complex. In addition, we also tested the known sGC inhibitor, ODQ, within the chronic nitroglycerin migraine model. Results VL-102-evoked acute and chronic mechanical cephalic and hind-paw allodynia in a dose-dependent manner, which was blocked by the migraine medications sumatriptan, propranolol, and topiramate. In addition, VL-102 also increased c-fos and CGRP expressing cells within the trigeminovascular complex. Importantly, ODQ completely inhibited acute and chronic hyperalgesia induced by nitroglycerin. ODQ also blocked hyperalgesia already established by chronic nitroglycerin, implicating this pathway in migraine chronicity. Conclusions These results indicate that nitroglycerin causes migraine-related pain through stimulation of the sGC pathway, and that super-activation of this receptor may be an important component for the maintenance of chronic migraine. This work opens the possibility for negative sGC modulators as novel migraine therapies.

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Moustafa, Amira, and Yoshiaki Habara. "Hydrogen sulfide: a novel gaseous signaling molecule and intracellular Ca2+ regulator in rat parotid acinar cells." American Journal of Physiology-Cell Physiology 309, no. 7 (October 1, 2015): C480—C490. http://dx.doi.org/10.1152/ajpcell.00147.2015.

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In addition to nitric oxide (NO), hydrogen sulfide (H2S) is recognized as a crucial gaseous messenger that exerts many biological actions in various tissues. An attempt was made to assess the roles and underlying mechanisms of both gases in isolated rat parotid acinar cells. Ductal cells and some acinar cells were found to express NO and H2S synthases. Cevimeline, a muscarinic receptor agonist upregulated endothelial NO synthase in parotid tissue. NO and H2S donors increased the intracellular Ca2+ concentration ([Ca2+]i). This was not affected by inhibitors of phospholipase C and inositol 1,4,5-trisphosphate receptors, but was decreased by blockers of ryanodine receptors (RyRs), soluble guanylyl cyclase, and protein kinase G. The H2S donor evoked NO production, which was decreased by blockade of NO synthases or phosphoinositide 3-kinase or by hypotaurine, an H2S scavenger. The H2S donor-induced [Ca2+]i increase was diminished by a NO scavenger or the NO synthases blocker. These results suggest that NO and H2S play important roles in regulating [Ca2+]i via soluble guanylyl cyclase-cGMP-protein kinase G-RyRs, but not via inositol 1,4,5-trisphosphate receptors. The effect of H2S may be partially through NO produced via phosphoinositide 3-kinase-Akt-endothelial NO synthase. It was concluded that both gases regulate [Ca2+]i in a synergistic way, mainly via RyRs in rat parotid acinar cells.

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Gong, R., C. Ding, J. Hu, Y. Lu, F. Liu, E. Mann, F. Xu, M. B. Cohen, and M. Luo. "Role for the Membrane Receptor Guanylyl Cyclase-C in Attention Deficiency and Hyperactive Behavior." Science 333, no. 6049 (August 11, 2011): 1642–46. http://dx.doi.org/10.1126/science.1207675.

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Weiglmeier, Philipp R., Paul Rösch, and Hanna Berkner. "Cure and Curse: E. coli Heat-Stable Enterotoxin and Its Receptor Guanylyl Cyclase C." Toxins 2, no. 9 (August 26, 2010): 2213–29. http://dx.doi.org/10.3390/toxins2092213.

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Basu, Nirmalya, Sayanti Saha, Imran Khan, Subbaraya G. Ramachandra, and Sandhya S. Visweswariah. "Intestinal Cell Proliferation and Senescence Are Regulated by Receptor Guanylyl Cyclase C and p21." Journal of Biological Chemistry 289, no. 1 (November 11, 2013): 581–93. http://dx.doi.org/10.1074/jbc.m113.511311.

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Mann, Elizabeth A., M. Lynn Jump, Jeffrey Wu, Elizabeth Yee, and Ralph A. Giannella. "Mice Lacking the Guanylyl Cyclase C Receptor Are Resistant to STa-Induced Intestinal Secretion." Biochemical and Biophysical Research Communications 239, no. 2 (October 1997): 463–66. http://dx.doi.org/10.1006/bbrc.1997.7487.

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Fowkes, RC, W. Forrest-Owen, and CA McArdle. "C-type natriuretic peptide (CNP) effects in anterior pituitary cell lines: evidence for homologous desensitisation of CNP-stimulated cGMP accumulation in alpha T3-1 gonadotroph-derived cells." Journal of Endocrinology 166, no. 1 (July 1, 2000): 195–203. http://dx.doi.org/10.1677/joe.0.1660195.

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C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, has been found at its highest tissue concentrations in the anterior pituitary, where it is localised in gonadotrophs. Its specific guanylyl cyclase-containing receptor, GC-B, is also expressed on several anterior pituitary cell types, and CNP potently stimulates cGMP accumulation in rat pituitary cell cultures and pituitary cell lines. The mouse gonadotroph-derived alpha T3-1 cell line has been shown to express CNP as well as GC-B (but not GC-A) receptors, suggesting that CNP may well be an autocrine regulator of gonadotrophs. Comparing effects of three natriuretic peptides (atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and CNP) on cGMP accumulation in four pituitary cell lines (alpha T3-1, TtT-GF, AtT-20 and GH(3)) we find that CNP is most potent and effective in alpha T3-1 cells. In these cells, CNP-stimulated cGMP accumulation was found to desensitise during a 30 min exposure to CNP. Pretreatment with CNP for up to 6 h also caused a significant reduction in the ability of CNP to subsequently stimulate cGMP accumulation. This effect was receptor specific, because pretreatment with sodium nitroprusside (an activator of nitric oxide-sensitive guanylyl cyclase), or with ANP or BNP, did not cause desensitisation of CNP-stimulated cGMP accumulation. Protein kinase C activation with phorbol esters also inhibited CNP-stimulated cGMP accumulation and such inhibition was also seen in cells desensitised by pretreatment with CNP. Thus it appears that the endogenous GC-B receptors of alpha T3-1 cells are subject to both homologous and heterologous desensitisation, that the mechanisms underlying these forms of desensitisation are distinct, and that cGMP elevation alone is insufficient to desensitise GC-B receptors.

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Omer, S., P. Vaillancourt, K. G. Peri, D. R. Varma, and S. Mulay. "Downregulation of renal atrial natriuretic factor receptors and receptor mRNAs during rat pregnancy." American Journal of Physiology-Renal Physiology 272, no. 1 (January 1, 1997): F87—F93. http://dx.doi.org/10.1152/ajprenal.1997.272.1.f87.

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Using renal glomeruli and papillae from virgin, pregnant (15- to 17-day), and postpartum (day 2) rats, we investigated whether the decrease in the renal effects of atrial natriuretic factor (ANF) during pregnancy is caused by a downregulation of ANF receptors. Pregnancy decreased the maximal binding of 125I-labeled ANF to guanylyl cyclase (GC)-linked ANF-GC receptors in glomeruli and papillae and increased the binding to clearance receptors (ANF-C) in glomeruli; ANF-C receptors were not detected in the papillae Ribonuclease protection assay detected mRNAs for all the three receptors in the papillae; pregnancy decreased GC-A and ANF-C but not GC-B-receptor mRNAs. Western blots revealed a decrease in GC-A receptors in the papillae of pregnant rats; GC-B-receptor protein was barely detectable. Effects of ANF on guanosine 3', 5'-cyclic monophosphate (cGMP) production by the glomeruli and papillae were decreased during pregnancy and returned to virgin levels during postpartum. It is concluded that a decrease in the renal effects of ANF during pregnancy is caused by a downregulation of renal ANF GC-A receptors and receptor-coupled cGMP production.

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PANDEY, Kailash N., Huong T. NGUYEN, Renu GARG, Madan L. KHURANA, and Jude FINK. "Internalization and trafficking of guanylyl (guanylate) cyclase/natriuretic peptide receptor A is regulated by an acidic tyrosine-based cytoplasmic motif GDAY." Biochemical Journal 388, no. 1 (May 10, 2005): 103–13. http://dx.doi.org/10.1042/bj20041250.

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We have identified a GDAY motif in the C-terminal domain of guanylyl cyclase (guanylate cyclase)/NPRA (natriuretic peptide receptor A) sequence, which serves a dual role as an internalization signal and a recycling signal. To delineate the role of the GDAY motif in receptor internalization and sequestration, we mutated Gly920, Asp921 and Tyr923 to alanine residues (GDAY/AAAA) in the NPRA cDNA sequence. The cDNAs encoding wild-type and mutant receptors were transfected in HEK-293 cells (human embryonic kidney 293 cells). The internalization studies of ligand–receptor complexes revealed that endocytosis of 125I-ANP by HEK-293 cells expressing G920A, Y923A or GDAY/AAAA mutant receptor was decreased by almost 50% (P<0.001) when compared with cells expressing the wild-type receptor. However, the effect of D921A mutation on receptor internalization was minimal. Ligand-mediated down-regulation of G920A, Y923A and GDAY/AAAA mutant receptors was decreased by 35–40% when compared with wild-type NPRA. Subsequently, the recycling of internalized D921A and GDAY/AAAA mutant receptors from the intracellular pool was decreased by more than 40±4% when compared with wild-type NPRA. Recycling of G920A and Y923A mutant receptors was also decreased, but to a significantly lesser extent compared with the D921A or GDAY/AAAA mutant receptors. We conclude that the Gly920 and Tyr923 residues within the GDAY consensus motif are necessary for internalization, and that residue Asp921 is important for recycling of NPRA. The current results provide new evidence for a dual role of the GDAY sequence motif in ligand-mediated internalization, recycling and down-regulation of a single-transmembrane receptor protein NPRA.

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48

Skorecki, K. L., A. S. Verkman, C. Y. Jung, and D. A. Ausiello. "Evidence for vasopressin activation of adenylate cyclase by subunit dissociation." American Journal of Physiology-Cell Physiology 250, no. 1 (January 1, 1986): C115—C123. http://dx.doi.org/10.1152/ajpcell.1986.250.1.c115.

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Radiation inactivation is used to probe the sequence of subunit interactions involved in the activation of adenylate cyclase by vasopressin in cultured renal epithelial cells (LLC-PK1) based on our previous analysis of the radiation inactivation of multimeric enzymes [Verkman et al., Am. J. Physiol. 250 (Cell Physiol. 19): C103-C114, 1986]. For basal adenylate cyclase activity, a concave downward ln(activity) vs. dose relation was observed with limiting slope corresponding to a molecular weight of (169-196) X 10(3). Similar results were obtained with NaF. In contrast, addition of vasopressin, guanylyl imidodiphosphate, or forskolin resulted in transition to a linear ln(activity) vs. dose relation with a slope corresponding to a molecular weight similar to that observed for basal activity. These findings were incorporated into a cyclic dissociation model for the hormonal activation of adenylate cyclase (graph see text) where H is hormone, R is receptor, C is catalytic unit, alpha and beta are subunits of guanyl nucleotide-regulatory protein (G), GTP is guanosine triphosphate, and GDP is guanosine diphosphate. The addition of H favors the dissociation of G into alpha and beta subunits by providing a rapid pathway for addition of GTP to dissociated alpha subunits. The observed target size of the active enzyme species formed corresponds to the composite molecular weights of alpha GTP with C. This model consolidates the radiation inactivation findings as well as the known biochemical characteristics for adenylate cyclase.

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Rao, S. P., Z. Sellers, D. L. Crombie, D. L. Hogan, E. A. Mann, D. Childs, S. Keely, et al. "A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion." American Journal of Physiology-Gastrointestinal and Liver Physiology 286, no. 1 (January 2004): G95—G101. http://dx.doi.org/10.1152/ajpgi.00087.2003.

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Luminal acidification provides the strongest physiological stimulus for duodenal [Formula: see text] secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated [Formula: see text] secretion. Previous studies in the rat and human duodenum have shown that guanylin and Escherichia coli heat-stable toxin, both ligands of the transmembrane guanylyl cyclase receptor [guanylate cyclase C (GC-C)], are potent stimulators for duodenal [Formula: see text] secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated [Formula: see text] secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal [Formula: see text] secretion was significantly decreased in the GC-C KO animals compared with the WT counterparts. Pretreatment with PD-98059, an MEK inhibitor, resulted in attenuation of duodenal [Formula: see text] secretion in response to acid stimulation in the WT mice with no further effect in the KO mice. In vitro cGMP generation studies demonstrated a significant and comparable increase in cGMP levels on acid exposure in the duodenum of both WT and KO mice. In addition, a rapid, time-dependent phosphorylation of ERK was observed with acid exposure in the duodenum of WT mice, whereas a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. On the basis of these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal [Formula: see text] secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal [Formula: see text] secretion.

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50

Wang, Yakun, Nana Kong, Na Li, Xiaoqiong Hao, Kaiwen Wei, Xi Xiang, Guoliang Xia, and Meijia Zhang. "Epidermal Growth Factor Receptor Signaling-Dependent Calcium Elevation in Cumulus Cells Is Required for NPR2 Inhibition and Meiotic Resumption in Mouse Oocytes." Endocrinology 154, no. 9 (June 20, 2013): 3401–9. http://dx.doi.org/10.1210/en.2013-1133.

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In preovulatory ovarian follicles, the oocyte is maintained in meiotic prophase arrest by natriuretic peptide precursor C (NPPC) and its receptor natriuretic peptide receptor 2 (NPR2). LH treatment results in the decrease of NPR2 guanylyl cyclase activity that promotes resumption of meiosis. We investigated the regulatory mechanism of LH-activated epidermal growth factor (EGF) receptor signaling on NPR2 function. Cumulus cell-oocyte complex is cultured in the medium with 30 nM NPPC to prevent oocyte spontaneous maturation. In this system, EGF could stimulate oocyte meiotic resumption after 4 hours of incubation. Further study showed that EGF elevated intracellular calcium concentrations of cumulus cells and decreased cGMP levels in cumulus cells and oocytes, and calcium-elevating reagents ionomycin and sphingosine-1-phosphate mimicked the effects of EGF on oocyte maturation and cGMP levels. EGF-mediated cGMP levels and meiotic resumption could be reversed by EGF receptor inhibitor AG1478 and the calcium chelator bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid, tetra(acetoxymethyl)-ester. EGF also decreased the expression of Npr2 mRNA in cumulus cells, which may not be involved in meiotic resumption, because the block of NPR2 protein de novo synthesis by cycloheximide had no effect on NPPC and EGF-mediated oocyte maturation. However, EGF had no effect on oocyte maturation when meiotic arrest was maintained in the present of cGMP analog 8-bromoadenosine-cGMP. These results suggest that EGF receptor signaling induces meiotic resumption by elevating calcium concentrations of cumulus cells to decrease NPR2 guanylyl cyclase activity.

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Journal articles on the topic 'Receptor guanylyl cyclase C'

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