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J. Biol. Chem., Vol. 276, Issue 9, 6057-6060, March 2, 2001

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MINIREVIEW
Guanylyl Cyclase-linked Natriuretic Peptide Receptors: Structure and Regulation^*

Lincoln R. Potter^§ and Tony Hunter

From the  Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, St. Paul, Minnesota 55108 and the Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, San Diego, California 92186

	INTRODUCTION

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

In 1956, two seemingly disparate but profoundly prophetic papers were published. Kisch (1) observed that atrial, but not ventricular, cardiac cells contain a highly developed Golgi network, reminiscent of a secretory system, and Henry and colleagues (2) discovered that elevated left atrial pressure stimulates urine output. Twenty-five years later the connection between these studies and the heart and the kidney was made when de Bold and colleagues (3) determined that rat atrial extracts contain a potent diuretic and natriuretic factor. Since the publication of this landmark paper in 1981, three structurally related but genetically distinct peptides with vasodilatory properties, called atrial natriuretic factor, also known as atrial natriuretic peptide (ANP),¹ brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) have been purified and molecularly cloned (4, 5) (Fig. 1).

View larger version (45K): [in this window] [in a new window]   Fig. 1.   Model of the structures and functions of natriuretic peptides and their receptors. See text for description. Numbering is for rat sequences. Drawings are not to scale.

The primary signaling molecules for these hormones are natriuretic peptide receptor-A (NPR-A) and natriuretic peptide receptor-B (NPR-B) (Fig. 1). They are members of the cell-surface family of guanylyl cyclase receptors, enzymes that catalyze the synthesis of the intracellular second messenger, cGMP (5, 6). Hence, they are sometimes referred to as guanylyl cyclase-A and guanylyl cyclase-B or GC-A and GC-B. NPR-A is activated by physiologic concentrations of ANP and BNP, but not CNP (7, 8). Conversely CNP, but not ANP or BNP, activates NPR-B (7, 8). In addition, all three natriuretic peptides bind the natriuretic peptide clearance receptor (NPR-C). In many tissues, NPR-C is the most abundant of the three natriuretic peptide receptors, and it binds ANP, BNP, and CNP with relatively similar affinities (9). It has only 37 intracellular amino acids and does not possess guanylyl cyclase activity. It is thought to primarily control the local concentrations of natriuretic peptides that are available to bind NPR-A and NPR-B (9), but a signaling function for this receptor has also been reported (10). In this review, we summarize the available data on the structure and regulation of NPR-A and NPR-B.

	Receptor Structure, Topology, and Oligomeric State

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

The basic topology of NPR-A and -B consists of an ~450-amino acid extracellular ligand-binding domain, a 21-residue hydrophobic membrane-spanning region, and a 566- or 568-amino acid intracellular domain, respectively (Fig. 1). The latter can be further divided into a juxtamembrane region of ~250 amino acids that is similar to known protein kinases called the kinase homology domain (KHD), a 41-amino acid amphipathic coiled-coil hinge region, and a roughly 250-amino acid C-terminal guanylyl cyclase catalytic domain. In the absence of ligand, NPR-A exists as a homodimer or homotetramer, and ANP binding does not lead to further aggregation (11-13). Multiple domains that are located both outside and inside the plasma membrane mediate the oligomerization of NPR-A. The intracellular dimerization interface region has been mapped to the amphipathic sequence that bisects the KHD and cyclase domains (14). The deletion of this region results in monomeric and inactive intracellular constructs, suggesting that dimerization of the cyclase domains is required for catalytic activity. NPR-B is also an oligomer in the absence of ligand (15).

The disulfide bonding structure of an extracellular secreted version of rat NPR-A has been determined (16). In this receptor, intramolecular bonds were found between Cys-60 and Cys-86, Cys-164 and Cys-215, and Cys-423 and Cys-432. Hence, the NPR-A extracellular domain contains three intramolecular but no intermolecular disulfide bonds. Two groups have addressed the role of the juxtamembrane cysteines in NPR-A. Labrecque et al. (17) found that the conversion of Cys-423 to serine resulted in a receptor variant that migrated at twice the molecular weight of the wild-type receptor under nonreducing but not reducing SDS-polyacrylamide gel electrophoresis conditions. They concluded that the removal of Cys-423 allowed Cys-432 to form an intermolecular disulfide bond with the corresponding residue on a separate polypeptide chain. This mutant's basal activity is elevated 20-40-fold compared with the wild-type receptor but has a diminished ability to be activated by ANP and/or ATP. In separate experiments, Huo and colleagues (18) found that the mutation of both Cys-423 and Cys-432 to serine results in a variant with similar guanylyl cyclase properties as the single Cys-423 mutant. Together, these data emphasize the importance of the juxtamembrane intrachain disulfide bond in NPR-A activation and suggest the increased basal activity observed with the Cys-423 mutant results from the loss of an intramolecular disulfide bond, not from the creation of an intermolecular disulfide bond. Studies of the disulfide binding pattern of NPR-B have not been reported, but because the cysteines involved in the N-terminal (Cys-53 and Cys-79) and juxtamembrane disulfide bonds (Cys-417 and Cys-426) are conserved between NPR-A and NPR-B, it is likely that these bonds form in NPR-B as well. A middle disulfide bond might be formed between Cys-205 and Cys-314 because these are the only remaining Cys residues in the extracellular domain of this receptor.

The crystal structure of the glycosylated, unliganded, dimerized hormone-binding domain of NPR-A has been solved at 2.0-Å resolution (19). The monomer consists of two interconnected subdomains, each encompassing a central -sheet flanked by -helices, and exhibits a type I periplasmic binding protein fold. Dimerization appears to be mediated by juxtaposition of 2 × 2 parallel helices that bring the two protruding C termini in close proximity. Affinity-labeling experiments indicated that residues 4 and 18 of ANP bind in the vicinity of Met-173 of NPR-A and that the C terminus of ANP binds near His-195. The assignment of receptor contact residues by the crystallography group is consistent with a previous report demonstrating that the amino portion of ANP could be cross-linked to the NPR-A chymotryptic peptide Met-173 to Phe-188 (20). The structure of an ANP-NPR-A complex has not been solved, but van den Akker et al. (19) speculate that the dimeric receptor contains two spatially separated ANP-binding sites, which yields a ligand-receptor stoichiometry of 2:2. This is consistent with previous studies that indicated the stoichiometry of binding is 1:1 (21, 22) or 2:2 (23) but not with a study that suggested a stoichiometry of 1:2 (24). Perhaps the most surprising finding to come from the initial structural work on NPR-A is the presence of an apparent chloride-binding site buried within the N-terminal portion of each monomer. Surprisingly, Misono (25) reported that chloride is absolutely required for ANP binding to the extracellular domain of NPR-A. Whether chloride is required for hormone binding to the full-length receptor or to NPR-B or NPR-C remains to be determined. In addition, whether chloride binding is reversible and therefore regulatory also remains to be answered. However, because the chloride concentration that is necessary for 50% of the maximal ANP binding response (EC₅₀ = 0.6 mM) is 2 orders of magnitude below physiologic concentrations, this appears unlikely.

Presently, no direct data are available on the crystal structure of any guanylyl cyclase catalytic domain. However, because of the high sequence similarity between the catalytic domains of adenylyl and guanylyl cyclases, the latter have been molecularly modeled based on the coordinates from the former (26). Both cyclase domains appear to form a wreathlike structure with the mammalian adenylyl cyclases and soluble guanylyl cyclases containing one active site per heterodimer and the membrane guanylyl cyclases, including NPR-A and NPR-B, containing two active sites per homodimer (27). Because the residues that interact with ribose, triphosphate, and Mg²⁺ in adenylyl cyclase are conserved in guanylyl cyclases, it is believed they serve similar functions in both enzymes. Hence, the residues that interact with the purine base determine substrate specificity. In the model of the nucleotide-binding site of the retinal guanylyl cyclase (ret-GC-1 or GC-E), Glu-925 and Cys-997 are essential for nucleotide discrimination and are envisioned to form critical hydrogen bonds with the N-1, N-2, and O-6 atoms of guanine, respectively (26). This model has now been tested and confirmed by Tucker and colleagues (28), who changed the substrate specificity of retinal guanylyl cyclase-1 from guanine to adenine by mutating Glu-925 and Cys-997 to Lys and Asp, the corresponding residues in adenylyl cyclases. These residues are conserved in NPR-A and NPR-B and are likely to serve similar functions in their active sites as well.

	Glycosylation

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

NPR-A purified from transfected ³⁵S-labeled 293 cells displays considerable size heterogeneity (13). The explanation for this variability is incomplete N-linked glycosylation because N-glycosidase treatment collapses all the higher molecular weight forms to a single species of ~116 kDa, the expected molecular mass of the core polypeptide (13). Direct sequencing of the N termini of human NPR-IgG fusion proteins purified from Chinese hamster ovary cells indicated that Asn-2 and Asn-13 of NPR-A and Asn-2 of NPR-B are glycosylated (29). In Cos-1 cells, an extracellular truncation mutant of rat NPR-A was found to be glycosylated at positions Asn-13, Asn-180, Asn-306, Asn-347, and Asn-395 (30). Asn-2 is not conserved in the rat version of NPR-A. Enzymatic deglycosylation of the extracellular domain of NPR-A does not significantly affect its ANP binding properties (30). In contrast, Fenrick and colleagues (31) determined that only the fully glycosylated form of NPR-B could be cross-linked to ¹²⁵I-CNP. Furthermore, cotransfection with truncated versions of NPR-B or unrelated receptors that decreased the amount of the fully glycosylated form of NPR-B, presumably by saturating the cellular glycosylation machinery, reduced its ability to produce cGMP in response to CNP (31). Mutational analysis of the asparagines present in the extracellular domain of bovine NPR-B suggested that five of the seven total sites are glycosylated, and the mutation of Asn-2 reduced CNP binding by 90%, presumably because of improper receptor folding (32). Collectively, these results suggest that glycosylation is required for proper receptor folding or targeting, but not for NP binding.

	Phosphorylation

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

The first direct indication that NP receptors are regulated by protein phosphorylation came in 1992 when NPR-A purified from metabolically labeled HEK 293 cells was shown to contain ³²P (33, 34). The stoichiometry of phosphate to receptor molecules was not determined, but the fact that dephosphorylation resulted in a slight electrophoretic mobility shift indicated that it is at least 1:1 (33). Despite the homology of the NPR-A KHD to the tyrosine kinase domain of the platelet-derived growth factor receptor, phosphoamino acid analysis detected only phosphoserine and phosphothreonine (33-35). When whole cells or membrane preparations containing the NPR-A were incubated with ANP or the purified catalytic subunit of protein phosphatase 2A, respectively, the receptor was dephosphorylated in parallel with losses in ANP-dependent guanylyl cyclase activity (33). NPR-A isolated from resting 293 cells is phosphorylated on six residues (Ser-497, Thr-500, Ser-502, Ser-506, Ser-510, Thr-513) located within the glycine-rich elbow and putative ATP-binding region of its KHD (36). Replacement of any of these phosphorylated amino acids, but not residues flanking this region, with alanine results in decreased ANP-dependent guanylyl cyclase activities (36). Receptors lacking four or more of these sites are completely unresponsive to hormone. NPR-B is also regulated by phosphorylation (37) and has five known phosphorylation sites within the N-terminal portion of its KHD (Thr-513, Thr-516, Ser-518, Ser-523, Ser-526) (38). These data indicate that receptor phosphorylation is not merely modulatory but is absolutely required for NP signal transduction. The NP receptor kinase has not been identified.

	Receptor Activation

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

As a starting point for the molecular analysis of NP-dependent activation and desensitization of NPR-A, we have constructed a working model of this process (Fig. 2). In the absence of NP, the receptor exists as a homodimer or homotetramer. It is highly phosphorylated, and its guanylyl cyclase activity is tightly repressed. Upon NP binding, the oligomeric state of the receptor does not change (12, 39), which indicates that receptor activation is not simply the result of ligand-dependent receptor oligomerization as is the case for many growth factor receptors. On the other hand, ANP binding does cause the extracellular juxtamembrane region of NPR-A to become susceptible to protease cleavage (18), which suggests that hormone binding induces a conformational change in this proline-rich "hinge" portion of the receptor. Exactly how hormone binding transmits an activation signal across the membrane is unclear. However, because ATP is required for maximal NP-dependent activation and receptors lacking the KHD are constitutively active in the absence of ANP (40), one possibility is that hormone binding facilitates ATP binding to the KHD. Once ATP is bound, a conformational change occurs within the KHD that facilitates three subsequent events. First, the normal inhibitory effect that the KHD has on catalytic activity is relieved and the guanylyl cyclase domains are allowed to come together to form two active sites per dimer. Second, an increased dissociation rate decreases the affinity of the extracellular domain of NPR-A for ANP. This effect also requires the KHD and is observed in whole cells as a time-dependent shift from high to low affinity ANP binding (41). Third, the conformational change in the KHD may expose the phosphorylated residues to a constitutively active, or perhaps a cGMP-activable, protein phosphatase. In addition, the ATP-bound KHD may be a poorer substrate for the NPR-A kinase. The resulting dephosphorylated receptor is unresponsive to further hormonal stimulation.

View larger version (38K): [in this window] [in a new window]   Fig. 2.   Hypothetical model of the activation and homologous desensitization of NPR-A. See text for description.

In contrast to ATP, the diuretic drug amiloride stabilizes the high affinity binding state and inhibits the hormone-dependent cyclase activity of NPR-A (41, 42). Because high concentrations of amiloride inhibit the ATP-dependent activation of NPR-A, it has been suggested that ATP and amiloride compete for the same site (41). However, amiloride, but not the ATP, modulated the affinity of NPR-A for ANP in preparations that were subjected to limited trypsin proteolysis, suggesting that amiloride and ATP bind to different sites (24). The location of the ATP-binding site has not been determined, but it may reside within the NPR-A polypeptide because ATP analogs modestly activate guanylyl cyclase (43) and inhibit NP binding activities (44) of highly purified receptor preparations. The ⁵⁰³GXGXXXG⁵⁰⁹ sequence within the KHD has been suggested to be the location of ATP interaction because of its similarity to the consensus ATP binding motif (GXGXXG) found in many protein kinases. In fact, this region has been dubbed the ATP regulatory domain or "ARM" by some investigators to emphasize its putative regulatory role (45). However, no direct ATP binding or cross-linking studies have been presented to support this hypothesis. These negative results are not unexpected because the EC₅₀ for ATP activation of NPR-A in guanylyl cyclase assays is ~0.1 mM (46). Hence, if this EC₅₀ is reflective of its binding constant for NPR-A, ATP may not bind tightly enough to obtain positive binding or cross-linking data. Regardless, this glycine motif is not required for ATP binding because the conversion of all three glycines to alanine has little or no effect on the activation of NPR-A (34). Other mutations within this region do decrease hormone-dependent activity, but they likely result from reductions in the phosphorylation state of the receptor (38).

	Homologous Desensitization

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

Because synthetic BNP (Nesiritide) has proven to be clinically beneficial in the treatment of congestive heart failure (47), an understanding of the mechanisms involved in the desensitization of these receptors is important from a basic science and a clinical perspective. Hormone-dependent activities of NPR-A and NPR-B can be reduced by chronic exposure to NPs, known as homologous desensitization, or by exposure to agents other than NPs, referred to as heterologous desensitization. Homologous desensitization can be divided into processes that are or are not mediated by receptor degradation, such as down-regulation and dephosphorylation, respectively. Mechanistic analysis of the homologous desensitization of NPR-A and NPR-B has been hampered by the fact that these receptors are often found in cells that also express NPR-C. Hence, losses in NP binding could theoretically result from the down-regulation of the cyclase-linked receptors, NPR-C, or both. In addition, because of the high affinity of these receptors for ligands, prebound NP can mask their ability to bind subsequent NP, a process known as prior receptor occupation (48). This phenomenon can lead to an underestimate of the amount of receptor present in cells and the erroneous conclusion that they are degraded when, in fact, their binding sites are masked.

One study that attempted to circumvent these potential pitfalls employed human embryonic kidney 293 cells that stably express NPR-A but have no detectable NPR-B or NPR-C (33). Metabolic labeling of these cells with [³²P]orthophosphate indicated that NPR-A is highly phosphorylated in the absence of NPs and that ligand exposure results in a time-dependent dephosphorylation and desensitization of the receptor. The phosphorylation state of the receptor was tightly correlated with its hormone-dependent guanylyl cyclase activity. The decreased ³²P signal was not explained by protein degradation because ANP exposure did not significantly reduce the amount of NPR-A purified from cells that were labeled with [³⁵S]Met/Cys. In a separate study, tryptic phosphopeptide maps of overexpressed NPR-A from NIH-3T3 cells indicated that ANP exposure did not stimulate the dephosphorylation of a specific phosphopeptide, although it clearly resulted in the dephosphorylation of the receptor (35). A similar scenario was reported for NPR-B (37). One explanation for these observations is that cells exposed to NP contain two pools of receptors, one that is maximally phosphorylated and another that is completely dephosphorylated. Another possibility is that all phosphorylation sites are dephosphorylated to an equal extent in hormone-exposed cells.

Homologous desensitization of NPR-A has been observed in vitro as well. Foster and Garbers (49) demonstrated that ATPS but not the nonhydrolyzable ATP analog, AMPPNP, could sensitize NPR-A to subsequent stimulation by ANP and AMPPNP in crude membranes, an effect that presumably results from the limited ability of protein phosphatases to dephosphorylate thiophosphorylated substrates. They also found that the serine/threonine protein phosphatase inhibitor, microcystin, could prolong the maintenance of the initial rate of the reaction and increase the total amount of cGMP formed in guanylyl cyclase assays, again suggesting that dephosphorylation was sufficient for desensitization. To determine whether NPR-A was the target of the phosphatase, all six phosphorylation sites were mutated to glutamate to mimic a constitutively phosphorylated form of NPR-A (NPR-A-6E) (50). This receptor, but not one containing analogous alanine mutations, is stimulated 10-fold by ANP and ATP. In contrast to the wild-type receptor, NPR-A-6E is activated equally well by ATP and AMPPNP and is completely unaffected by microcystin. These data suggest that the superior ability of ATPS and ATP to activate NPR-A results from their ability to serve as substrates in a protein kinase reaction and that the protein that is being dephosphorylated in the in vitro cyclase assay is the receptor itself. Furthermore, NPR-A-6E, which cannot shed its negative charge via dephosphorylation, was shown to be resistant to homologous desensitization (50). These results indicate that NPR-A and NPR-B are homologously desensitized by receptor dephosphorylation, a unique paradigm compared with most G-protein-coupled receptors that are desensitized by direct phosphorylation.

	Heterologous Desensitization

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

The vasoconstrictory hormones arginine-vasopressin, angiotensin II, and endothelin, which activate protein kinase C (PKC) through the stimulation of phospholipase C, antagonize the actions of natriuretic peptides and decrease both ANP- and CNP-dependent cGMP elevations in cultured cell lines (51-53). The reduced cGMP concentrations result from a calcium-dependent increase in phosphodiesterase activity (52, 54) and a PKC-dependent decrease in guanylyl cyclase activity (35, 52, 55). Activation of PKC appears to be necessary and sufficient for the latter effect because phorbol 12-myristate 13-acetate (PMA), a direct activator of PKC, mimics and inhibitors of PKC block the ability of these hormones to desensitize natriuretic peptide receptors (35, 52, 55). The antagonism between these systems exists in the absence of strong PKC activators as well because the down-regulation of PKC by chronic exposure to PMA (56) or angiotensin II (48) results in the sensitization of NPR-A to ANP. Hence, the activities of NPR-A and NPR-B are under the constant surveillance of the renin-angiotensin as well as other PKC-activating systems.

Studies involving in vitro phosphorylation of NPR-A in crude membranes suggested that PKC directly phosphorylates NPR-A (57). However, interpretation of these observations is complicated by subsequent studies employing specific antibodies in which activation of PKC in whole cells resulted in the dephosphorylation, not phosphorylation, of NPR-A (35). Unlike the global dephosphorylation associated with the homologous process, the heterologous desensitization is associated with the dephosphorylation of a single site or small subset of the total. Currently the identity of this site(s) within NPR-A is not known. PMA exposure results in the selective dephosphorylation of Ser-523 in NPR-B and reduces both basal and hormone-dependent cyclase activities (58). Importantly, replacement of this amino acid with alanine or glutamate abolished the inhibition, indicating that dephosphorylation of this single serine residue accounts for heterologous desensitization of NPR-B. Consistent with these data are results of Chrisman and Garbers (59) showing that platelet-derived growth factor treatment of mouse fibroblasts results in the dephosphorylation and desensitization of NPR-B. Because this growth factor signals, in part, by activating PKC via phospholipase C, dephosphorylation of Ser-523 may be instrumental in this process as well. Whether the PKC-dependent dephosphorylation of NPR-A and NPR-B results from the activation of a protein phosphatase or the inhibition of a protein kinase is not known nor is the identity of the responsible protein kinase or phosphatase.

Finally, although both homologous desensitization and heterologous desensitization are mediated by dephosphorylation, several observations suggest that each pathway is unique. First, homologous but not heterologous desensitization requires NP binding. Second, heterologous but not homologous desensitization requires PKC (35, 55). Third, homologous desensitization involves global receptor dephosphorylation, whereas the heterologous process results in the loss of single phosphate (35). Last, the combined effect of ANP and PMA is greater than either alone, indicating that these processes are additive (35, 55). Whether each process involves the same or a different protein kinase and phosphatase remains to be determined.

	Future Directions

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

Over the past 15 years much has been learned about the location, structure, and physiologic function of NPR-A and NPR-B (4-6). Within the next few years it is likely that molecules will be discovered that regulate these NP receptors. Clearly the NP receptor kinase and phosphatase are prime candidates for identification. Because phosphorylation is obligatory for the activation of NPR-A and NPR-B, loss of function mutations within the enzyme(s) that mediates this process may yield phenotypes similar to those of animals lacking NPs. Hence, it is possible that some forms of idiopathic hypertension or dwarfism may be explained by mutations in the NP receptor kinase. Likewise, activating mutations within the NP receptor phosphatase may result in these diseases. The identification of proteins that regulate NPR-A and NPR-B may provide additional drug targets for the treatment of these and other diseases.

	ACKNOWLEDGEMENTS

We are grateful to the many people who communicated results prior to publication and apologize to those whose work we were unable to reference because of space limitations. We thank Sarah Abbey and Jamie Simon for help with the figures.

	FOOTNOTES

^* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001.

^§ To whom correspondence should be addressed: Dept. of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 356 Gortner Laboratory, 1479 Gortner Ave., St. Paul, MN 55108. Tel.: 612-624-7251; Fax: 612-624-7282; E-mail: Potter@tc.umn.edu.

Published, JBC Papers in Press, January 10, 2001, DOI 10.1074/jbc.R000033200

	ABBREVIATIONS

The abbreviations used are: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide; HEK, human embryonic kidney; KHD, kinase homology domain; NP, natriuretic peptide; NPR-A, natriuretic peptide receptor A; NPR-B, natriuretic peptide receptor B; GC, guanylyl cyclase; ATPS, adenosine 5'-O-(thiotriphosphate); AMPPNP, adenosine 5'-(, -imino)triphosphate; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate.

	REFERENCES

TOP INTRODUCTION Receptor Structure, Topology,... Glycosylation Phosphorylation Receptor Activation Homologous Desensitization Heterologous Desensitization Future Directions REFERENCES

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				L. M. Hunt, E. W. Hogeland, M. K. Henry, and S. J. Swoap Hypotension and bradycardia during caloric restriction in mice are independent of salt balance and do not require ANP receptor Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1446 - H1451. [Abstract] [Full Text] [PDF]

				J. R. Dietz, C. S. Landon, S. J. Nazian, D. L. Vesely, and W. R. Gower Jr. Effects of Cardiac Hormones on Arterial Pressure and Sodium Excretion in NPRA Knockout Mice Experimental Biology and Medicine, September 1, 2004; 229(8): 813 - 818. [Abstract] [Full Text] [PDF]

				G. E. Woodard, X. Li, and J. A. Rosado Water deprivation enhances the inhibitory effect of natriuretic peptides on cAMP synthesis in rat renal glomeruli Am J Physiol Renal Physiol, September 1, 2004; 287(3): F418 - F426. [Abstract] [Full Text] [PDF]

				D. Rahmutula, J. Cui, S. Chen, and D. G. Gardner Transcriptional Regulation of Type B Human Natriuretic Peptide Receptor Gene Promoter: Dependence on Sp1 Hypertension, September 1, 2004; 44(3): 283 - 288. [Abstract] [Full Text] [PDF]

				Z. Zhou, S. Gross, C. Roussos, S. Meurer, W. Muller-Esterl, and A. Papapetropoulos Structural and Functional Characterization of the Dimerization Region of Soluble Guanylyl Cyclase J. Biol. Chem., June 11, 2004; 279(24): 24935 - 24943. [Abstract] [Full Text] [PDF]

				L. R. Potter CNP, Cardiac Natriuretic Peptide? Endocrinology, May 1, 2004; 145(5): 2129 - 2130. [Full Text] [PDF]

				S. E. Abbey-Hosch, A. N. Cody, and L. R. Potter Sphingosine-1-Phosphate Inhibits C-Type Natriuretic Peptide Activation of Guanylyl Cyclase B (GC-B/NPR-B) Hypertension, May 1, 2004; 43(5): 1103 - 1109. [Abstract] [Full Text] [PDF]

				D. Muller, A. K. Mukhopadhyay, R. C. Speth, G. Guidone, R. Potthast, L. R. Potter, and R. Middendorff Spatiotemporal Regulation of the Two Atrial Natriuretic Peptide Receptors in Testis Endocrinology, March 1, 2004; 145(3): 1392 - 1401. [Abstract] [Full Text] [PDF]

				T. Langenickel, J. Buttgereit, I. Pagel, R. Dietz, R. Willenbrock, and M. Bader Forced Homodimerization by Site-Directed Mutagenesis Alters Guanylyl Cyclase Activity of Natriuretic Peptide Receptor B Hypertension, February 1, 2004; 43(2): 460 - 465. [Abstract] [Full Text] [PDF]

				T. Chitapanarux, S. L. Chen, H. Lee, A. C. Melton, and H. F. Yee Jr. C-type natriuretic peptide induces human colonic myofibroblast relaxation Am J Physiol Gastrointest Liver Physiol, January 1, 2004; 286(1): G31 - G36. [Abstract] [Full Text] [PDF]

				C. Sengenes, A. Bouloumie, H. Hauner, M. Berlan, R. Busse, M. Lafontan, and J. Galitzky Involvement of a cGMP-dependent Pathway in the Natriuretic Peptide-mediated Hormone-sensitive Lipase Phosphorylation in Human Adipocytes J. Biol. Chem., December 5, 2003; 278(49): 48617 - 48626. [Abstract] [Full Text] [PDF]

				M. Kuhn Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A Circ. Res., October 17, 2003; 93(8): 700 - 709. [Abstract] [Full Text] [PDF]

				N. Airhart, Y.-F. Yang, C. T. Roberts Jr., and M. Silberbach Atrial Natriuretic Peptide Induces Natriuretic Peptide Receptor-cGMP-dependent Protein Kinase Interaction J. Biol. Chem., October 3, 2003; 278(40): 38693 - 38698. [Abstract] [Full Text] [PDF]

				A. Yamazaki, H. Yu, M. Yamazaki, H. Honkawa, I. Matsuura, J. Usukura, and R. K. Yamazaki A Critical Role for ATP in the Stimulation of Retinal Guanylyl Cyclase by Guanylyl Cyclase-activating Proteins J. Biol. Chem., August 29, 2003; 278(35): 33150 - 33160. [Abstract] [Full Text] [PDF]

				I. Ben-Shlomo, S. Yu Hsu, R. Rauch, H. W. Kowalski, and A. J. W. Hsueh Signaling Receptome: A Genomic and Evolutionary Perspective of Plasma Membrane Receptors Involved in Signal Transduction Sci. Signal., June 17, 2003; 2003(187): re9 - re9. [Abstract] [Full Text] [PDF]

				A. De Lean, N. McNicoll, and J. Labrecque Natriuretic Peptide Receptor A Activation Stabilizes a Membrane-distal Dimer Interface J. Biol. Chem., March 21, 2003; 278(13): 11159 - 11166. [Abstract] [Full Text] [PDF]

				S. E. Abbey and L. R. Potter Lysophosphatidic Acid Inhibits C-Type Natriuretic Peptide Activation of Guanylyl Cyclase-B Endocrinology, January 1, 2003; 144(1): 240 - 246. [Abstract] [Full Text] [PDF]

				S. E. Abbey and L. R. Potter Vasopressin-dependent Inhibition of the C-type Natriuretic Peptide Receptor, NPR-B/GC-B, Requires Elevated Intracellular Calcium Concentrations J. Biol. Chem., November 1, 2002; 277(45): 42423 - 42430. [Abstract] [Full Text] [PDF]

				R. Middendorff, D. Muller, M. Mewe, A. K. Mukhopadhyay, A. F. Holstein, and M. S. Davidoff The Tunica Albuginea of the Human Testis Is Characterized by Complex Contraction and Relaxation Activities Regulated by Cyclic GMP J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3486 - 3499. [Abstract] [Full Text] [PDF]

				C. Sengenes, A. Zakaroff-Girard, A. Moulin, M. Berlan, A. Bouloumie, M. Lafontan, and J. Galitzky Natriuretic peptide-dependent lipolysis in fat cells is a primate specificity Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R257 - R265. [Abstract] [Full Text] [PDF]

				D. D. Doyle, J. Upshaw-Earley, E. L. Bell, and H. C. Palfrey Natriuretic peptide receptor-B in adult rat ventricle is predominantly confined to the nonmyocyte population Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2117 - H2123. [Abstract] [Full Text] [PDF]

				P. M. Bryan and L. R. Potter The Atrial Natriuretic Peptide Receptor (NPR-A/GC-A) Is Dephosphorylated by Distinct Microcystin-sensitive and Magnesium-dependent Protein Phosphatases J. Biol. Chem., May 3, 2002; 277(18): 16041 - 16047. [Abstract] [Full Text] [PDF]

				M H Sarker and P A Fraser The role of guanylyl cyclases in the permeability response to inflammatory mediators in pial venular capillaries in the rat J. Physiol., April 1, 2002; 540(1): 209 - 218. [Abstract] [Full Text] [PDF]

				D. Muller, R. Middendorff, J. Olcese, and A. K. Mukhopadhyay Central Nervous System-Specific Glycosylation of the Type A Natriuretic Peptide Receptor Endocrinology, January 1, 2002; 143(1): 23 - 29. [Abstract] [Full Text] [PDF]

				X.-l. He, D.-c. Chow, M. M. Martick, and K. Christopher Garcia Allosteric Activation of a Spring-Loaded Natriuretic Peptide Receptor Dimer by Hormone Science, August 31, 2001; 293(5535): 1657 - 1662. [Abstract] [Full Text] [PDF]

				D. D. Doyle, J. Upshaw-Earley, E. L. Bell, and H. C. Palfrey Natriuretic peptide receptor-B in adult rat ventricle is predominantly confined to the nonmyocyte population Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2117 - H2123. [Abstract] [Full Text] [PDF]

				M.H. Sarker and P. A. Fraser The role of guanylyl cyclases in the permeability response to inflammatory mediators in pial venular capillaries in the rat J. Physiol., February 15, 2002; (2002) 200101291. [Abstract] [PDF]

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