Receptors of atrial natriuretic factor.

ANNUAL REVIEWS

Further

Quick links to online content Annu. Rev. Physiol. 1992.54:11-27 Copyright © 1992 by Annual Reviews Inc. All rights reserved

RECEPTORS OF ATRIAL

Annu. Rev. Physiol. 1992.54:11-27. Downloaded from www.annualreviews.org by Nanyang Technological University on 05/24/14. For personal use only.

NATRIURETIC FACTOR Thomas Maack Department of Physiology and Cardiovascular Center, Cornell University Medical College, New York, New York 10021 KEY WORDS:

biological receptors of ANF, clearance receptors of ANF, guanylate cyclase, cOMP, second messengers of ANF

INTRODUCTION Atrial natriuretic factor (ANF) is a polypeptide hormone that is secreted mainly by the heart atria in response to increases in atrial pressure or atrial stretch. ANF has multiple actions in the kidney that lead to increases in glomerular filtration rate and excretion of fluid and electrolytes, modulation of renal vascular resistance, decreases in inner medullary hypertonicity and sodium reabsorption by tubular epithelial cells, and stimulation of sodium secretion in inner medullary collecting duct cells. ANF also modulates systemic vascular resistance, inhibits the renin-angiotensin-aldosterone sys tem, and decreases arterial blood pressure, cardiac output and plasma volume (for a general review on the functional properties of ANF see Reference 11). Not surprisingly, after the initial reports in 1984 that showed the presence of high affinity specific binding sites of ANF in kidney cortex, aorta, and adrenal glomerulosa (30, 71), and the finding that ANF increases cGMP by activation of a membrane bound (particulate) guanylate cyclase (70, 107, 110), workers performed intensive and extensive studies on the distribution and the biochemical and functional properties of ANF receptors. These studies brought many novel concepts on receptor structure and function, whose full implication is still not understood. In this chapter, the main findings of these studies on ANF receptors and second messengers are considered in a brief and non-inclusive manner. 11

0066-4278/92/0315-0011$02.00


12

MAACK

There are two major biochemically and functionally distinct classes of ANF. Biological receptors proper, named type B, type I (R1), or guanylate cyclase (GC) receptors, mediate the known functional effects of the hormone and have as their main second messenger cyclic(c) GMP. Two major sub types of B-ANF receptors have been described, and they are named BA (or GCA) and Ba (or GCa) receptors. The other major class of ANF receptors, type C or type I1(R2) receptors, is unique among polypeptide receptors because it does not mediate any of the known end organ effects (e.g. natriuresis, vasodilation) of the hormone, but it has an important role in the removal of ANF from the circulation, hence the name clearance (C) receptors. C-ANF receptors are by far the most abundant class of ANF receptors, comprising more than 95% of the total ANF receptor population in kidney cortex and vascular tissues.

DISTRIBUTION AND HETEROGENEITY OF ANF RECEPTORS Overall Distribution Autoradiographic studies demonstrate that ANF receptors are present in most tissues of the mammalian organism, including kidney, vasculature, adrenal, lung, intestine, and brain (15, 48, 67, 89, 93). Within the kidney, the highest density of ANF-binding sites is localized in glomeruli, but a significant density of ANF receptors is also present in the inner stripe of the outer medulla and in the papilla (15, 48, 56, 67). Within glomeruli, auto radiographic studies at the electron-microscopic level indicate that the binding sites are localized to epithelial cells (16), whereas in the renal medulla, ANF receptors are localized in bundles of descending vasa recta, inner medullary collecting ducts, and interstitial cells (14). Radioligand binding assays further reveal that ANF receptors are particularly abundant in rat kidney cortex (71, 104, 111), glomeruli (12, l7), vascular smooth muscle and endothelial cells (40, 51, 52, 96, 98), lung tissue (44) and lung fibroblasts (50, 51), re nomedullary interstitial cells from the rat (32), and adrenal cortex (30, 66, 6 9).

Receptors Heterogeneity The existence of ANF receptor- heterogeneity was first suggested by ex periments in cultured bovine aortic vascular smooth muscle (BAVSM) and endothelial (BAE) cells, which showed that there is a poor correlation be tween the total number of ANF receptors detected by radioligand binding assays (BAVSM, ca. 200,000--600,000 sites/cell; BAE, ca. 10,000-200,000


ANF RECEPTORS

13

sites/cell) and the maximal ANF-induced increase in cGMP (BAVSM, ca. 8s-fold; BAE, ca. 6-fold) (96). Furthermore, in these cells, C-terminal deleted analogues of native ANF (ANFI-28), such as ANF5-25 (atriopeptin I), were able to displace the overwhelming majority of radiolabeled ANFI_28 from its binding sites; however, these analogues had a weak cGMP generating activity and did not alter the dose-response curve of the cGMP generating effect of ANFI_28 (54, 96). Cross-linking and photoaffinity labeling studies reveal the existence of at least two specific binding proteins for ANF in cell membranes from kidney cortex, adrenal cortex, vascular smooth muscle, and endothelial cells (51,52, 69, 95, 97, 109, 111). Under non-reducing conditions, two labeled bands, migrating at 120-130 and 60-70 kd, were visualized by polyacrylamide gel electrophoresis (SDS-PAGE), whereas under reducing conditions there was a marked shift to the 60-70 kd band with a diminution, and sometimes almost complete disappearance, of the 120--130 kd band. In BAVSM and BAE cells, excess unlabeled ANFI_28 fully displaced 125I-ANFI_28 from both the 60 and 120 kd bands, whereas excess atriopeptin I displaced label only from the 60 kd band. It is now clear from cloning experiments (see below) that the 120 kd protein is the B-ANF receptor, whereas the C-ANF receptor is a homodimer also of 120 kd (60 kd under reducing conditions). Some investigators have also reported the presence of even higher molecular weight forms (140 and 180 kd) of B-ANF receptors by SDS-PAGE (84). It is not clear, however, whether these higher molecular weight proteins represent different sub-types of B-ANF receptors or are simply more extensively glycosylated forms of the 120-130 kd B-ANF receptor.

Distribution of Receptor Sub-Types In cultured vascular smooth muscle, endothelial cells, and fibroblasts, more than 90% and, in some instances more than 98%, of the total population of ANF receptors consists of C-ANF receptors (40, 50-52, 96, 98). Equilibrium displacement binding studies in isolated perfused rat kidney show that C-ANF receptors also constitute the overwhelming majority (> 95%) of the total population of ANF receptors in whole kidney tissue and in kidney cortex, whereas they constitute only ca. 50% of ANF receptors in the renal papilla (59). In isolated glomeruli, both major sub-types of ANF receptors are present, with C-ANF receptors constituting approximately 70% of the total ANF receptor population in rat glomeruli (64, 74). Consistent with the binding studies showing the presence of B-ANF receptors, ANF induces a major dose-dependent increase in cGMP in isolated glomeruli from rats (12, 19, 72, 74), dogs (103, 107), and humans (9). There is conflicting evidence regarding the localization of ANF receptors within glomeruli. An early

14

MAACK

autoradiographic study in the rat seemed to indicate a predominant localiza tion in glomerular epithelial rather than in mesangial cells

(16). However,

glomerular mesangial cells in culture have a high density of ANF receptors

(12, 23, 74), and it was reported that cultured glomerular epithelial cells from the rat fail to express a significant density of ANF receptors (12). On the other hand, ANF markedly increases cGMP generation in human cultured glomeru lar epithelial cells, whereas it has only minimal effects on cultured human mesangial cells

(10). These discrepancies could reflect species differences or,


more likely, changes in receptor expression under different culture con ditions. In any event, the ANF-induced increase in cGMP in cultured rat mesangial cells has a clear functional counterpart in its relaxant effect on these cells

(8). There is no known functional counterpart for the ANF-induced

increase in cGMP in glomerular epithelial cells. Studies in isolated dissected nephron segments, cultured cells, or freshly isolated cells consistently demonstrate ANF-induced increases in cGMP in inner medullary collecting duct cells, albeit not to the same magnitude as in glomerular or renomedullary interstitial cells

(32, 72, 112). In other tubular

segments, ANF binding and ANF-induced increases in cGMP are minor, if present. Several investigators found no ANF binding or ANF-induced in crease in cGMP generation in any nephron segment upstream to the inner medullary collecting ducts

(15, 17, 19, 20, 42, 62, 107). In the rat, one group

reported minor ANF-induced increases in cGMP in practically all proximal and distal nephron segments upstream to the inner medullary collecting duct (IMCD)

(72). It is noteworthy that cultured renal medullary interstitial cells

from the rat have the highest density of B-ANF receptors and the largest absolute ANF-induced increase in cGMP reported to date

(32). The functional

meaning of the large concentration of B-ANF receptors in these cells is at present unclear

(32).

STRUCTURE-BINDING-ACTIVITY RELATIONSHIPS B-ANF receptors have rather stringent structural requirements for ligand binding. Disruption of the disulfide bridge, deletion of C-terminal Phe-Arg (Tyr) , or amino acid deletions or substitutions within the ring structure of ANFI_28 impair binding to B-ANF receptors

(1, 51, 52, 60, 81, 94-96). The

C-terminal tyrosine residue and the N-terminal portion of ANF are less important since, for example, ANFs_27 and ANF5--28 (atriopeptin

II and III) as

well as ANF4--27 and ANF4--28 (auriculin A and B) are as effective ligands of B-ANF receptors as native ANFl-28

(58).

C-ANF receptors have much less stringent structural requirements for ligand binding. A wide variety of deleted or substituted atrial peptide an-

ANF RECEPTORS

15

alogues bind to C-ANF receptors with relatively high affinity, including peptides with complete deletion of the C- and N-terminal tails, D-amino acid substitutions or amino acid deletions within the ring-structure of ANF, and linear peptides containing as few as five amino acids from the N-terminal region of the ring structure of ANF (1,51,52,60,81,94-96). Among the truncated analogues, des [Glnls, Serl9, Gly-20, Leu21, Gly22]rANF4--zrNHz,


simply referred to as C-ANF4-- 3, became the prototype of a specific ligand for 2 C-ANF receptors (59). This synthetic peptide binds to C-ANF receptors with almost the same affinity as ANF1_Z8, does not generate cGMP or antagonize the cGMP-generating effect of ANF, even at very high concentrations, and does not mediate any of the known renal and cardiovascular actions of ANF

(57, 59, 60), C-ANF4--Z3 was instrumental in the discovery of the clearance function of C-ANF receptors (see below). Apparently, the minimal amino acid sequence necessary for binding to C-ANF receptors. comprises the 11-15 sequence of the native ANF molecule, namely, Argll, He12, Asp13, Argl4, lIels (79). This lack of stringency for ligand binding is an unusual property since receptors generally are thought to have much more strict structural requirements for their ligands. Nevertheless, C-ANF receptors are unable to bind peptides not related to the family of atrial peptides and are, therefore, specific for ANF, brain natriuretic peptide (BNP), and the recently discovered CNP (47).

PURIFICATION, CLONING, AND MOLECULAR CHARACTERISTICS OF ANF RECEPTORS Purification of B-ANF Receptors B-ANF receptors from BAE cells have been purified to apparent homogene ity, and in each step of the purification procedure, ANF binding and guanylate cyclase activity were found to co-elute in the same chromatographic fractions

(49). This striking finding, which was confirmed by several other studies using membrane preparations from the same and other cells and tissues (21, 43, 53, 84, 105), led to the postulate that B-ANF receptors and particulate (membrane bound) guanylate cyclase were in fact the same protein (53), an hypothesis that was fully confinned when the B-ANF receptor was cloned and sequenced (see below).

Cloning and Biochemical Characteristics of C-ANF Receptors C-ANF receptors were purified from cultured BASVM cells, and a partial sequence of the solubilized receptor was determined (97). Screening of a eDNA library from BAVSM cells, using oligonucleotide probes based on this partial sequence, eventually led to the determination of the entire coding

sequence of the C-ANF receptor (33). C-ANF receptors were the first of the


16

MAACK

ANF receptors to be cloned and fully sequenced (33). The mature receptor ,subunit has 496 amino acids with a Mr of 55,701, consistent with the estimated Mr of C-ANF receptors in cross-linking and photoaffinity labeling experiments, followed by SDS-PAGE under reducing conditions. Hydropac ity plots indicate that C-ANF receptors have a single transmembrane domain, a large extracellular domain, and a very short cytoplasmic tail of 37 amino acids, of which 5 are potential phosphorylation sites. The extracellular do main has two pairs of cysteine residues, one isolated cysteine near the transmembrane domain, three potential signals for N-glycosylation, and several serines and threonines that could contain O-linked carbohydrates (33). There is no significant homology between the amino acid sequence of C-ANF receptors and that of any other sequenced protein, except the extracellular domain of BA-ANF receptors (see below). Noteworthy is the shortness of the cytoplasmic domain of C-ANF receptors, a common feature of all other known clearance or transport receptors such as lipoprotein, transferrin, and asialo-glycoprotein receptors (73). The mRNA for C-ANF receptors has been identified in several tissues in mammalian species including humans (33). C-ANF receptors from bovine vascular smooth muscle cells have been ex pressed in Xenopus oocytes and in mammalian (L-M, CVl, and MCDK) cells, and the receptors expressed in these heterologous systems exhibited the same ligand properties and lack of cGMP response to ANF as native C-ANF receptors (87, 88). Recently, C-ANF receptors from human kidney have also been characterized biochemically, and the amino acid sequence was found to be practically identical to that of C-ANF receptors from BAVSM cells (86). Cloning and Molecular Structure of B-ANF Receptors B-ANF receptors were cloned and sequenced in studies that initially em ployed a cDNA probe encoding a soluble guanylate cyclase of the sea urchin (26). In this manner, the entire coding region of guanylate cyclase from a rat brain cDNA library was obtained. COS-7 cells transfected with this cloned cDNA expressed a protein that has a high affinity for ANFI_28, but a very low affinity for ANFs--2S. The transfected cells showed a higher guanylate cyclase activity and responded to ANF by increasing the generation of cGMP (26). Thus the cloned receptor had the typical characteristics previously described for native B-ANF receptors. The BA (GCA) receptor cloned in these ex periments has 1057 amlno acids with a Mr of 115,852, a putative single transmembrane spanning region, and large intracellular (567 amino acids) and extracellular (441 amino acids) domains. The extracellular domain has 33% homology with that of C-ANF receptors from BAVSM cells, including the preserved pairs of cysteines. This homology may explain why ANFI_28 binds with similar high affinity to B-ANF and C-ANF receptors. The intracellular domain of the BA-ANF receptor is unique among membrane receptors. It

ANF RECEPTORS

17

contains a 253-amino acid sequence near the carboxyl tenninus that is similar to those of soluble guanylate cyclase and of brain adenylate cyclase. Thus, as initially postulated, B-ANF receptors contain within a single molecule a binding domain and guanylate cyclase activity, thereby being unique among known receptors in that they are directly able to generate a small second messenger. In addition, the cytoplasmic domain has an amino acid sequence (256 amino acids) adjacent to the membrane that is 31% homologous with the tyrosine kinase domain of the PDGF receptor (25, 26). In all likelihood this


domain plays a regulatory role as a repressor for the guanylate cyclase activity since its mutational deletion leads to maximal activation of guanylate cyclase and, consequently, to unresponsiveness to ANF (25). It has also been sug gested that ATP, which increases the

Vrnax of ANF-stimulated membrane

guanylate cyclase activity possibly by binding to the protein kinase domain, stabilizes a derepressed confonnation of the B-ANF receptor (25). It is of interest tbaumiloride iIJCIea�Jhe affinity of B-ANF receptors of the adrenal cortex, possibly by interfering with ATP binding at the protein kinase domain (65). Screening of a human placental cDNA library with cDNA probes of soluble guanylate cyclase derived from sea urchin unveiled the presence of another sub-type of B-ANF receptors (BB or GCB receptor) (22, 100). Whereas the cytoplasmic domain of the cloned BB-ANF receptor has striking homology with that of BA-ANF receptors, there are considerable differences in the extracellular domain. Consequently, BB-ANF receptors display a different hierarchy of binding for atrial peptides. Thus when expressed in COS-7 cells, these receptors have a higher binding affinity for brain natriuretic peptide than for atrial natriuretic factor. However, its affinity for BNP, albeit higher than that for ANF, is so low (in the,uM range) that it is unlikely that BB receptors can serve as the physiological receptor for either peptide class in vivo. One possible candidate for the endogenous physiological ligand of BB-ANF recep tor is CNP, a recently described novel member of the natriuretic peptide family (47). It has been assumed that BB-ANF receptors are confined to nervous tissues (47), but further work is needed to clarify the distribution as well as the physiological role of BB-ANF receptors.

THE CLEARANCE FUNCTION OF C-ANF RECEPTORS The discovery that C-ANF receptors have a major role in the removal of ANF from the circulation originated from experiments in the isolated perfused rat kidney, which demonstrated that a specific ligand of C-ANF receptors,

C-ANF4-23, at concentrations that led to occupancy of > 95% of the total ANF receptor population in whole kidney tissue and in the kidney cortex, did not have intrinsic biological effects of its own and did not antagonize any of

18

MAACK

the known renal vascular, hemodynamic, and excretory effects of native ANFl_28 (59). This led to the concept that C-ANF receptors are biologically silent, meaning that they do not mediate any of the known renal or vascular effects of ANF

(59, 60). The observation that C-ANF receptors function as

clearance receptors arose from this same study, which showed that when C-ANF4-23 was administered to intact anesthetized or conscious rats, plasma

levels of endogenous immunoreactive ANF increased in a reversible manner. This increase led to natriuretic and blood pressure lowering effects that


followed the rise and fall in plasma levels of endogenous hormone (59, 60). These effects of C-ANF4-23 on renal function and blood pressure were quantitatively undistinguishable from those of an infusion of native ANF 1-28 that increased plasma levels of the hormone to the same degree as that

obtained with an infusion of the C-ANF receptor ligand (59). Recently it was reported that other ligands of C-ANF receptors, including small linear pep tides containing as few as five amino acids of the ring structure of ANF, have essentially the same effects of C-ANF4-23 when administered to anesthetized rats (79). The decisive evidence that demonstrated that C-ANF receptors exert an important clearance function came from pharmacokinetics experiments show ing that blockade of C-ANF receptors by infusion of C-ANF4-23 markedly decreases the volume of distribution at steady-state (Vss) and the metabolic

clearance rate (MCR) of infused 125I-ANFI_28 in a dose-related manner in the

(2). At the maximal dose of C-ANF4-23 (10 p.g/minlkg body weight), Vss decreased to one third and MCR decreased to one fourth of their control

rat

values. This decrease accounts entirely for the fourfold increase in plasma

l evels of endogenous ANF at the highest dose of C-ANF4-23. Recently, these results were fully confirmed by another group of in vestig at ors (27). In the above mentioned pharmacokinetics study, it was also estimated that the relative proportion of occupied C-ANF receptors at normal plasma con centrations of ANF was only ca. one one-hundreth of the total number of C-ANF receptors in the rat

(2).

The pharmacokinetics experiments described above also reveal that block

ade of C-ANF receptors in vivo leads to an inhibition of the delayed appear

ance of labeled ANF metabolites (mainly 12sI-monoiodotyrosine) after the administration of 125I-ANFI_28

(2, 27). This finding is consistent with a

process of receptor-mediated endocytosis and lysosomal hydrolysis of en docytosed ANF. Recently the cellular mechanisms of the clearance function

of C-ANF receptors were elucidated in experiments in cultured BAVSM cells

(73). This study demonstrated that C-ANF receptors are rapidly internalized together with 125I_ANF 1-�8 and, after a short lag time, the internalized radioligand is hydrolyzed to amino acids within lysosomes. Following in ternalization of the receptor-ligand complex and dissociation of this complex


ANF RECEPTORS

19

within endosomes, C-ANF receptors are rapidly recycled to the cell surface. Similar to what occurs with other clearance and/or transport receptors, in ternalization and recycling of C-ANF receptors are constitutive processes, i.e. they do not depend on ligand binding (73). From these and other data of this study it was calculated that the entire population of C-ANF receptors in BASVM cells (220,000-400,000 sites/cell) is internalized and recycled every hour (73). Consequently, there is no detectable down-regulation of C-ANF receptors in these cells during short (up to 2 hr) exposure to high con centrations of ligand. Although homologous down-regulation was initially suggested to occur with elevated plasma levels of ANF in rats fed a high salt diet or in hypertensive rats, more recent studies show that this apparent down-regulation is due to receptor occupancy by ANF rather than actual decrease in the density of C-ANF receptors (64, 99). The endocytic properties of C-ANF receptors and their ability to mediate lysosomal hydrolysis of ligand sharply contrast with that of B-ANF receptors. Indeed, it was recently reported that B-ANF receptors are not internalized and do not mediate hydrolysis of ANF in glomerular mesangial and renomedullary interstitial cells (46). C-ANF receptors essentially behave as a hormonal buffer system impeding large inappropriate fluctuations in plasma levels of ANF. The studies de scribed above show that the C-ANF receptors effectively perform this role and mediate the removal of ANF from the circulation because of their (a) very high affinity for ANF, such that there is receptor occupancy even at normal plasma concentrations of the hormone; (b) very high density, such that there is a great excess of C-ANF receptors; (c) strategic location in tissues and cells (vascular smooth muscle cells, endothelial cells, and kidney glomeruli) that receive a large proportion of the cardiac output; and (d) rapid recycling of internalized receptors to the cell surface, which makes the same receptor molecule available for the mediation of several cycles of internalization and lysosomal hydrolysis of ANF. ANF is also metabolized in vitro by renal brush border neutral endopepti dase (EC 3.4. 24-11) (102), and inhibitors of endopeptidase (NEP) were shown to potentiate the natriuretic effect of ANF in vivo (63, 80, 106). These findings led investigators to postulate that in vivo metabolism of ANF results from its hydrolysis by NEP. However, peptide analogues that bind to C-ANF receptors, but are fully resistant to the actions of NEP in vitro, are removed from the rat plasma at the same rate as native ANF (1). Furthermore, in most instances, inhibition of NEP in the rat does not increase plasma levels of endogenous immunoreactive ANF (63, 80, 106) or decrease the metabolic clearance of administered 125I-ANFI_28 (27, 78). Finally, the potentiating effect of NEP inhibitors on the natriuretic effects of ANF in the rat is fully blocked by the administration of a bradykinin receptor antagonist (101). This


20

MAACK

latter finding suggests that local increases in bradykinin, rather than of ANF, are responsible for the potentiating effect of NEP inhibitors. In view of the above, it is likely that C-ANF receptor-mediated removal of ANF from the circulation and C-ANF receptor-mediated hydrolysis of ANF take precedence over metabolic processes mediated by endopeptidases. ANF is the first polypeptide hormone for which a specific class of receptors, biochemically distinct from the biological receptors proper, function as clearance receptors. There are, however, multiple sub-types of receptors for practically every polypeptide hormone studied so far, and many of these sub-types have presently an unknown function. While it is possible that at least some of them have an important role in the removal and plasma homeostasis of their specific ligands, direct evidence for this is lacking. Potentially, blockade of C-ANF receptors may constitute an important therapeutic approach to elevate plasma levels of endogenous ANF. The recent development of small linear peptide analogues of ANF (78, 79) raises the hope that orally active ligands of C-ANF receptors may be available in the near future. Whether C-ANF receptor ligands could lead to chronic sustained elevations of plasma levels of ANF, natriuresis, and decrease in blood pressure remains to be demonstrated.

SECOND MESSENGERS In all studies reported to date, ANF markedly increases cGMP in target tissues and in plasma in a dose-related manner (12,29,36,72,76, 107, 110, 112). Furthermore, analogues of cGMP mimic the vasorelaxant action of ANF (70, 110) and the changes in sodium transport in renal cells (18, 55, 92, 112). There is an apparent major discrepancy regarding the role of cGMP as mediator of the aldosterone-lowering effect of ANF since some analogues of cGMP, such as dibutyril cGMP, do not mimic this action in adrenal zonal glomerulosa cells (31). Recently it was found that other analogues such as 8-bromo cGMP are able to inhibit ACTH-induced aldosterone secretion by lowering cAMP levels via a cGMP-dependent increase in cAMP phospho diesterase activity (61). The recent finding that B-ANF receptors contain guanylate cyclase activity in a single molecule (see above) adds a decisive piece of evidence indicating that cGMP is the principal second messenger of ANF. The cellular mechanisms by which cGMP mediates the actions of ANF are poorly understood. In vascular smooth muscle, glomerular mesangial, and adrenal zona glomerulosa cells, ANF and cGMP reduce agonist or de polarization-induced increases in cytosolic Ca2+ (7, 24, 37, 38, 68). It is known that cGMP activates sarcolemmal Ca2+ -ATPase, and this event may participate importantly in the ANF-induced decrease in cytosolic Ca2+ in


ANF RECEPTORS

21

vascular smooth muscle cells (85, 90). Apparently ANF does not alter calcium entry or the sodium-calcium exchange mechanism (45, 110). In vascular smooth muscle cells, endothelial cells, and the isolated perfused IMCD, both ANF and cGMP stimulate the Na-2CI-K cotransporter (75, 82, 92). This event may explain the increase in sodium secretion observed in isolated perfused IMCD preparations (92). ANF and cGMP also inhibit amiloride-sensitive uptake of Na+ in LLC-PK\ and IMDC cells (18, 55). This event, as well as the vascular smooth muscle effects of cGMP, may be due to stimulation of cGMP-activated protein kinase(s) (28, 55, 85). Although the above evidence adds substantial descriptive detail to the cellular actions of ANF and cGMP, present knowledge does not allow a firm mechanistic interpretation of any of the known cellular actions of ANF. Some investigators postulate that inhibition of cAMP is the primary event of the cellular actions of ANF in many tissues. One group in particular has reported that ANF inhibits adenylate cyclase in practically all membrane preparations tested, including those derived from vascular tissues, glomeruli, nephron segments (except proximal tubules), cardiac tissue, adrenal zona glomerulosa, and posterior pituitary (3-6). This effect is apparently mediated by activation of a pertussis-sensitive Gj protein at ANF concentrations lower than those necessary to activate guanylate cyclase or increase cGMP. On the other hand, the evidence of an inhibitory effect of ANF on basal or agonist induced increase in cAMP is contradictory, some investigators finding a decrease (3, 41, 61, 77, 83, 108) and others no change in this nucleotide (10, 12, 32, 72, 112). In isolated perfused proximal or distal nephron segments, investigators have consistently failed to detect an effect of ANF on cAMP generation (17, 72). In adrenal glomerulosa cells, ANF decreases cAMP via a cGMP-induced activation of a phosphodiesterase rather than an inhibition of adenylate cyc lase (61). Similarly, the ANF-induced decrease in cAMP in macrophages is also secondary to an increase in cGMP (34). Recently, it was claimed that the putative effects of ANF on adenylate cyclase activity are mediated by C-ANF rather than B-ANF receptors (4). It was also reported that ANF increases inositol phosphate turnover and hence calcium mobilization (39, 91), and one group of investigators claims that this effect is mediated by C-ANF receptors (39). It also appears that in cultured IMDC cells, a cell type that has B-ANF receptors, but apparently lacks C-ANF receptors (35), ANF increases phos pholipase C and IP3 at doses lower than those needed to increase cGMP (13). If IMDC cells have B-ANF but not C-ANF receptors, this evidence, if confirmed in fresh cells, would constitute unequivocal evidence that B-ANF receptors are able to mediate changes in inositol phosphate turnover. The fact that C-ANF receptors have an important clearance function and do not mediate the known renal and vascular effects of ANF (see above) does not


22

MAACK

preclude that they may generate second messengers and even exert some unknown cellular or organ actions. It must be pointed out, however, that whether the reported effects of ANF on adenylate cyclase, cAMP, or IP3 generation are mediated by B-ANF or C-ANF receptors, it seems unlikely that they play a primary role on the renal or vascular actions of the hormone. Indeed, in kidney and vascular tissues, inhibition of cAMP and increase in IP3 (effects that are known to be elicited for instance by angiotensin II) lead to vasoconstriction and antinatriuresis, effects that are opposite to those of ANF. This would be particularly true if these effects are mediated by C-ANF receptors, as has been claimed, since in these tissues there is an overwhelming proportion of these receptors compared to B-ANF receptors. Nonetheless, the possibility cannot be dismissed that inhibition of cAMP and/or an increase in IP3 facilitate the generation of cGMP by B-ANF receptors, perhaps, by interacting with the modulatory domains of these receptors. It is also possible that effects of ANF on cAMP andlor IP3 are secondary to the generation of cGMP and are involved in the turn-off rather than the turn-on of the hormonal responses. Whatever the case, it is certain that studies on second messengers and the mechanisms of cellular actions of ANF will command a central atten tion of investigators in the field in the next period. ACKNOWLEDGMENTS

The research of the author's laboratory has been supported by the National Institutes of Health grant ROI DK-14241. Literature Cited I. Adams, S. P., Fok, K. F., OJins, G. M., Trapani, A. J., Krieter, P. A., et aI.

Genest, J., Cantin, M. 1986. Effect of

1988 . Synthesis, activity and duration studies on pseudopeptide analogs of at rial natriuretic factor. In Biological and Molecular Aspects of Atrial Factors, P. Needleman, pp. 109-124. New York: Liss 2. Almeida, F. A., Suzuki, M., Scarbor ough, R. M., Lewicki, J. A., Maack, T. 1989. Clearance function of type C re ceptors of atrial natriuretic factor in rats. Am. J. Physiol. 256:R469-77 3. Anand Srivastava, M. B., Cantin, M., Genest, J. 1985. Inhibition of pituitary

atrial natriuretic factor on adenylate cyc lase in various nephron segments. Am. J. Physiol. 251:F417-22 6. Anand Srivastava, M. B., Srivastava, A. K., Cantin, M. 1987. Pertussis toxin attenuates atrial natriuretic factor mediated inhibition of adenylate cyc lase. Involvement of inhibitory-guanine nucleotide regulatory protein. J. Bioi. Chern. 262:4931-34 7. Appel, R. G., Dubyak, G. R., Dunn, M. J. 1987. Effect of atrial natriuretic factor on cytosolic free calcium in rat glomerular mesangial cells. FEBS. Lett.

factor. Life. Sci. 36: 1873-79 4. Anand-Srivastava, M. B., Sairam, M. R., Cantin, M. 1990. Ring-deleted an alogs of atrial natriuretic factor inhibit adenylate cyclase/cAMP system. Possi ble coupling of clearance atrial natriure tic factor receptors to adenylate cyclase/ cAMP signal transduction system. J. BioI. Chern. 265:8566-72 5. Anand Srivastava, M. B., Vinay, P.,

8. Appel, R. G., Wang, J., Simonson, M. S., Dunn, M. J. 1986. A mechanism by which atrial natriuretic factor mediates its glomerular actions. Am. J. Physiol. 251:FI03�2 9. Ardaillou, N., Nivez, M. P., Ardaillou, R. 1985. Stimulation of guanylate cyc lase by atrial natriuretic factor in isolated human glomeruli. FEBS. Lett. 189:8-12 10. Ardaillou, N., Nivez, M. P., Ardaillou,

adenylate cyclase by atrial natriuretic

224:396-400

ANF RECEPTORS

11.


12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

R. 1986. Stimulation of cyclic GMP synthesis in human cultured glomerular cells by atrial natriuretic peptide. FEBS. Lett. 204:177-82 Atlas, S. A., Maack, T. 1987. Effects of atrial natriuretic factor on the kidney and the renin-angiotensin-aldosterone sys tem. Endocrinol. Metab. Clin. North Am. 16:107-43 Ballermann, B. J., Hoover, R. L., Kar novsky, M. J., Brenner, B. M. 1985. Physiologic regulation of atrial natriure tic peptide receptors in rat renal glomeruli. J. Clin. Invest. 76:2049-56 Berl, T., Mansour, J., Teiltebaum, L 1991. ANP stimulates phospholipase C in cultured RMICT cells: roles of protein kinases and G protein. Am. J. Physiol. 260:F590--95 Bianchi, C., Gutkowska, J., Garcia, R., Thibault, G., Genest, J., Cantin, M. 1987. Localization of 125I-atrial natriuretic factor ANF-binding sites in rat renal medulla. A light and electron microscope autoradiographic study. J. Histochem. Cytochem. 35:149-53 Bianchi, C., Gutkowska, J., Thibault, G., Garcia, R., Genest, J., Cantin, M. 1985. Radioautographic localization of 125I-atrial natriuretic factor ANF in rat tissues. Histochemistrv 82:441-52 Bianchi, C, Gutkowska, J., Thibault, G., Garcia, R., Genest, J., Cantin, M. 1986. Distinct localization of atrial natriuretic factor and angiotensin II binding sites in the glomerulus. Am. J. Physioi. 251:F594-96 Butlen, D., Mistaoui, M., Morel, F. 1987. Atrial natriuretic peptide receptors along the rat and rabbit nephrons: [1251] alpha-rat atrial natriuretic peptide bind ing in microdissected glomeruli and tubules. Pflugers. Arch. 408:356-65 Cantiello, H. F., Ausiello, D. A. 1986. Atrial natriuretic factor and cGMP in hibit amiloride-sensitive Na + transport in the cultured renal epithelial cell line, LLC-PKI. Biochem. Biophys. Res. Commun. 134:852-60 Chabardes, D., Montegut, M., Mis taoui, M., Butlen, D., Morcl, F. 1987. Atrial natriuretic peptide effects on cGMP and cAMP contents in microdis sected glomeruli and segments of the rat and rabbit nephron. Pflugers Arch. 408:366-72 Chai, S. Y., Sexton, P. M., Allen, A. M., Figdor, R., Mendelsohn, F. A. 1986. In vitro autoradiographic localiza tion of ANP receptors in rat kidney and adrenal gland. Am. J. Physiol. 250:F753-57 Chang, C.-H., Kohse, K. P., Chang, B., Hirata, M., Jiang, B., et al. 1990.

23

Characterization of ATP-stimulated guanylate cyclase activation in rat lung membranes. Biochim. Biophys. Acta Mol. Cell Res. 1052:159-65 22. Chang, M. S., Lowe, D. G., Lewis, M., Hellmiss, R., Chen, E., Goeddel, D. V. 1989. Differential activation. by atrial and brain natriuretic peptides of two dif ferent receptor guanylate cyclases. Na ture 341 :68--72 23. Chansel, D., Pham, D. P., Nivez, M. P., Ardaillou, R. 1990. Characterization of atrial natriuretic factor receptors in human glomerular epithelial and mesan gial cells. Am. J. Physiol. 259:F619-27 24. Chartier, L., Schiffrin, E. L. 1987. Role of calcium in effects of atrial natriuretic peptide on aldosterone production in adrenal glomerulosa cells. Am. J. Physi01. 252:E485-89 25. Chinkers, M., Garbers, D. L. 1989. The protein kinase domain of the ANP recep tor is required for signaling. Science 245:1392-94 26. Chinkers, M., Garbers, D. L., Chang, M. S., Lowe, D. G., Chin, H. M., et aL 1989. A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor. Nature 338:78-83 27. Chiu, P. J. S., Tetzloff, G., Romano, M. T., Foster, C. J., Sybertz, E. J. 1991. Influence of C-ANF receptor and neutral endopeptidase on pharmacokine tics of ANF in rats. Am. J. Physiol. 260:R208-16 28. Cornwell, T. L., Lincoln, T. M. 1989. Regulation of Ca2+ levels in cultured vascular smooth muscle cells. Reduction of CaZ+ by atriopeptin and 8-bromo cyclic GMP is mediated by cyclic CMP dependent protein kinase. J. BioI. Chern. 264:1146-55 29. De Lean, A. 1986. Amiloride potenti ates atrial natriuretic factor inhibitory ac tion by increasing receptor binding in bovine adrenal zona glomerulosa. Life Sci. 39:1109-16 30. De Lean, A., Gutkowska, J., McNicoll, N., Schiller, P. W., Cantin, M., Genest, J. 1984. Characterization of specific re ceptors for atrial natriuretic factor in bovine adrenal zona glomerulosa. Life Sci. 35:2311-18 31. Elliott, M. E., Goodfriend, T. L. 1986. Inhibition of aldosterone synthesis by at rial natriuretic factor. Fed. Proc. 45:2376-81 32. Fontoura, B. M. A., Nussenzveig, D. R., Pelton, K. M., Maack, T. 1990. Atrial natriuretic factor receptors in cul tured renomedullary interstitial cells. Am. J. Physiol. 258:C692-99 33. Fuller, F., Porter, J. G., Arfsten, A. E., Miller, J., Schilling, J. W., et aL 1988.

24

34.

35.


36.

37.

38.

39.

40.

41.

42.

43. 44.

45.

MAACK Atrial natriuretic peptide clearance re ceptor. Complete sequence and func tional expression of eDNA clones. J. Bioi. Chern. 263:9395-9401 Garvin, J. L 1989. Inhibition of Jv by ANF in rat proximal straight tubules re quires angiotensin. Am. J. Physiol. 257:F907-11 Gunning, M., Silva, P. , Brenner, B. M. , Zeidel, M. L 1989. Characteristics of ANP-sensitive guanylate cyclase in inner medullary collecting duct cells. Am. J. Physiol. 256:F766-77 Hamet, P., Tremblay, J., Pang, S. C., Garcia, R., Thibault, G., et al. 1984. Effect of native and synthetic atrial natriuretic factor on cyclic GMP. B iochem. B iophys. Res. Commun. 123: 515-27 Hassid, A. 1986. Atriopeptin II de creases cytosolic free Ca in cultured vascular smooth muscle cells. Am. J. Physiol. 251:C681-86 Hassid, A 1987. Atriopeptins decrease resting and hormone-elevated cytosolic Ca in cultured mesangial cells. Am. J. Physiol. 253:FI077-82 Hirata, M., Chang, C. H., Murad, F. 1989. Stimulatory effects of atrial natriuretic factor on phosphoinositide hydrolysis in cultured bovine aortic smooth muscle cells. B iochim. B iophys. Acta 1010:34&-51 Hirata, Y, Takata, S. , Tomita, M. , Takaichi, S. 1985. Binding, internaliza tion, and degradation of atrial natriuretic peptide . in cultured vascular smooth muscle cells of rat. B iochem. B iophys. Res. Commun. 132:97&-84 Houdijk, A. P., Adolfs, M. J., Bonta, I. L, De longe, H. R. 1990. Atriopeptins and nitroprusside provoke opposite changes in cGMP and cAMP levels in human macrophages. Eur. J. Pharma col. 179:413-17 Huang, C L, Ives, H. E., Cogan, M. G. 1986. In vivo evidence that cGMP is the second messenger for atrial natriure tic factor. Proc. Narl. Acad. Sci. USA 83:8015-18 Inagami, T. 1989. Atrial natriuretic fac tor. J. B ioi. Chern. 264:3043-46 Ishido, M., Fujita, T., Hagiwara, H., Shimonaka, M., Saheki, T. , et aI. 1986. Physical and functional association of the atrial natriuretic peptide receptor with particulate guanylate cyclase as demonstrated using detergent extracts of bovine lung membranes. B iochem. B io phys. Res. Commun. 140:101-6 Kobayashi, S. , Kanaide, H. , Nakamura, M. 1985. Cytosolic-free calcium tran sients in cultured vascular smooth mus-

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

cle cells; microfluorimetric measure ments. Science 229:553-56 Koh, G. Y., Nussenzveig, D. R. , Okoli can y, I., Maack, T. 1991. Type B re ceptors of atrial natriuretic factor ANF do not mediate endocytosis and lyso somal hydrolysis of ANF in cultured glomerular mesangial and renomedul lary interstitial cells. FASEB J. 5;AI021 Koller, K. 1., Lowe, D. G., Bennett, G. L, Minamino, N., Kangawa, K. , et aI. 1991. Selective activation of B natriure tic peptide receptor by C-type natriuretic peptide CNP. Science 252:12�23 Koseki, C., Hayashi, Y., Torikai, S. , Furuya, M. , Ohnuma, N. , Imai, M. 1986. Localization of binding sites for alpha-rat atrial natriuretic polypeptide in rat kidney. Am. J. Physiol. 250: ( 2) F21�6 Kuno, T., Andresen, J. W., Kamisaki, Y., Waldman, S. A. , Chang, L. Y. et al. 1986. Co-purification of an atrial natriuretic factor receptor and particulate guanylate cyclase from rat lung. J. B ioi. Chern. 261:5817-23 Leitman, D. C. , Agnost, V. L. , Tuan, J. J., Andresen, J. W. , Murad, F. 1987. Atrial natriuretic factor and sodium nit roprusside increase cyclic GMP in cul tured rat lung fibroblasts by activating different forms of guanylate cyclase. B iochem. J. 244:69-74 Leitman, D. C. , Andresen, J. W. , Cata lano, R. M . , Waldman, S. A. , Tuan, J. J. , Murad, F. 1988. Atrial natriuretic peptide binding, cross-linking, and stimulation of cyclic GMP accumulation and particulate guanylate cyclase activ ity in cultured cells. J. B ioi. Chern. 263:3720-28 Leitman, D. C, Andresen, I. W. , Kuno, T., Kamisaki, Y., Chang, J. K. , Murad, F. 1986. Identification of multi ple binding sites for atrial natriuretic fac tor by affinity cross-linking in cultured endothelial cells. J. B ioi. Che rn. 261: 1165�55 Leitman, D. c., Molina, C. R. , Wald man, S. A., Murad, F. 1988. Atrial natriuretic peptide receptors and the guanylate cyclase-cyclic GMP system. See Ref. I, pp. 39-56 Leitman, D. C., Murad, F. 1986. Com parison of binding and cyclic GMP accumulation by atrial natriuretic pep tides in endothelial cells. B iochim. B io phys. Acta 885:74-79 Light, D. B. , Schwiebert, E. M., Karl son, K. H., Stanton, B. A. 1989. Atrial natriuretic peptide inhibits a cation chan nel in renal inner medullary collecting duct cells. Science 243:383-85


ANF RECEPTORS 56. Lynch, D. R., Braas, K. M., Snyder, S. H. 1986. Atrial natriuretic factor recep tors in rat kidney, adrenal gland , and brain: autoradiographic localization and fluid balance dependent changes. Proc. Natl. Acad. Sci. USA 83:3357-61 57. Maack, T., Almeida, F. A., Suzuki, M. , Nussenzveig, D. R. , Scarborough, R. M. , Lewicki, J. A. 1988. Physiolog ical role of atrial natriuretic factor recep tors. In Advances in Atrial Peptide Re search, B. M. Brenner, J. H. Laragh, pp. 25-30. New York: Raven 58. Maack, T . , Kleinert, H. D. 1986. Renal and cardiovascular effects of atrial natriuretic factor. Biochem. Pharmacal. 35:2059-64 59. Maack, T . , Suzuki, M. , Almeida, F. A., Nussenzveig, D., Scarborough, R. M. , et al. 1987. Physiological role of silent receptors of atrial natriuretic fac tor. Science 238:675-78 60. Maack, T . , Suzuki, M. , Nussenzveig, D. R. , Owada, A. , Scarborough, R. M. , et al. 1988 . Clearance receptors of atrial natriuretic factor. See Ref. I, pp. 57-76 61. MacFarland , R. T. , Zelus, B. D. , Be avo, J. A. 1 99 1 . High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. J. Bioi. Chem. 266: 136-42 62. Mantyh, C. R., Kruger, L., Brecha, N. C. , Mantyh, P. W. 1986. Localization of specific binding sites for atrial natriuretic factor in peripheral tissues of the guinea pig, rat, and human. Hypertension 8:712-21 63. Marleau, S. , Ong, H . , Brochu, M. , Yamaguchi, N., de Lean, A., Dusouich, P. 1990. Endogenous atrial natriuretic factor after endopeptidase 24. 1 1 inhibi tion by tiorphan. Peptides 1 1 :387-91 64. Martin, E. R., Lewicki, J. , Scarbor ough, R. M. , Ballerman, B. J. 1989. Expression and regulation of ANP re ceptors subtypes in rat renal glomeruli and papillae. Am. J. Physiol. 257:F64957 65. Meloche, S., McNicoll, N., Liu, B. , Ong, H . , De Lean, A. 1988. Atrial natriuretic factor R 1 receptor from bovine adrenal zona glomerulosa: purification, characterization, and mod ulation by amiloride. Biochemistry 27:8151-58 66. Meloche, S. , Ong, H . , Cantin, M. , De Lean, A. 1986. Affinity cross-linking of atrial natriuretic factor to its receptor in bovine adrenal zona glomerulosa. J. Bioi. Chem. 261 : 1525-28 67. Mendelsohn, F. A. , Allen, A. M. , Chai,

25

S. Y . , Sexton, P. M . , Figdor, R. 1987. Overlapping distributions of receptors for atrial natriuretic peptide and an giotensin II visualized by in vitro auto radiography: morphological basis of physiological antagonism. Can. J. Phy siol. Pharmacol. 65:1517-21 68. Meyer Lehnert, H . , Tsai, P. , Caramelo, c . , Schrier, R. W. 1988. ANF inhibits vasopressin-induced Ca2+ mobilization and contraction in glomerular mesangial cells. Am. J. Physiol. 255:F771-78 69. Misono, K. S., Grammer, R. T . , Rigby, J. W., Inagami, T. 1985. Photoaffinity labeling of atrial natriuretic factor recep tor in bovine and rat adrenal cortical membranes. Biochem . Biophys. Res. Commun . 130:994-1001 70. Murad, F. 1986. Cyclic guanosine monophosphate as a mediator of vasodilation. J. Clin . Invest. 78: 1-5 71. Napier, M. A., Vandlen, R. L., Albers Schonberg, G . , Nutt, R. F. , Brady, S. , et al. 1984. Specific membrane recep tors for atrial natriuretic factor in renal and vascular tissues. Proc. Natl. Acad. Sci. USA 8 1:5946-50 72. Nonoguchi, H., Knepper, M. A . , Man ganiello, V. C. 1987. Effects of atrial natriuretic factor on cyclic guanosine monophosphate and cyclic adenosine monophosphate accumulation in micro dissected nephron segments from rats. J. Clin . Invest. 79:500-7 73. Nussenzveig, D. R., Lewicki, J. A., Maack, T. 1990. Cellular mechanisms of the clearance function of type C re ceptors of atrial natriuretic factor. J. Bioi. Chem. 265 :20952-58 74. Nussenzveig, D. , Scarborough, R . , Lewicki, J . , Maack, T . 1988. Clearance receptors of atrial natriuretic factor (C ANF receptors) in isolated glomeruli and mesangial cells in culture. Kidney Int. 33:279 (Abstr.) 75. O ' Donnell, M. E. 1989. Regulation of Na-K-CI cotransport in endothelial cells by atrial natriuretic factor. Am. J. Physi01. 257:C36-44 76. Ohlstein, E. H., Berkowitz, B. A. 1985. Cyclic guanosine monophosphate medi ates vascular relaxation induced by atrial natriuretic factor. Hype rtension 7:30610 77. Okajima, F. , Kondo, Y. 1990. Inhibi tion of atrial natriuretic peptide-induced cGMP accumulation by purinergic agon ists in FRTL-5 thyroid cells. Involve ment of both pertussis toxin-sensitive and insensitive mechanisms. J. Bioi. Chem . 265:21741-48 78. Okolicany , J. , McEnroe, G . , Lewicki, J . , Koh, G. Y . , Maack, T. 1991. A

26

79.


80.

81.

82.

83.

84.

85.

86.

87.

88.

MAACK small peptide ligand of C-ANF recep tors, but not phosphoramidon, decreases metabolic clearance of ANF 1-28 in the rat. FASEB J. S:AI020 (Abstr.) Okolicany, I., McEnroe, G. A., Greg ory, L. C . , Lewicki, J. A . , Maack, T. 1 99 1 . Effects of small C-ANF receptor ligands on plasma levels of atrial natriuretic factor, blood pressure and re nal function in the rat. Can. J. Physiol. Pharmacol. In press Olins, G. M . , Krieter, P. A . , Trapani, A. J . , Spear, K. L., Bovy, P. R. 1989. Specific inhibitors of endopeptidase 24. 1 1 inhibit the metabolism of atrial natriuretic peptides in vitro and in vivo. Mol. Cell Endocrinol. 6 1 :201-8 Olins, G . M . , Patton, D. R . , Bovy, P. R . , Mehta, P. P. 1988. A linear analog of atrial natriuretic peptide ANP dis criminates guanylate cyclase-coupled ANP receptors from non-coupled recep tors. J. Bioi. Chern. 263 : 10989-93 Owen, N. E . , Bush, E. N . , Holleman, W . , O'Donnell, M. E. 1987. Effect of atrial natriuretic factor on Na+-K+-CI cotransport of vascular smooth muscle cells. Hypertension 10:11 28-23 Pandey, K. N . , Kovacs, W. J. , Inagami, T. 1985. The inhibition of progesterone secretion and the regulation of cyclic nucleotides by atrial natriuretic factor in gonadotropin responsive murine Leydig tumor cells. Biochern. Biophys. Res. Cornrnun. 133:S00-6 Paul, A. K . , Marala, R. B . , Jaiswal, R . K . , Sharma, R. K. 1987. Coexistence of guanylate cyclase and atrial natriuretic factor receptor in a I S0-kD protein. Sci ence 235 : 1224-26 Popescu, L. M . , Panoiu, C . , Hinescu, M . , Nutu, O. 1985. The mechanism of cGMP-induced relaxation in vascular smooth muscle. Eur. J. Pharmacol. 107:393-94 Porter, J. G . , Arfsten, A . , Fuller, F., Miller, J. A . , Gregory , L . C . , Lewicki, J. A. 1 990. Isolation and functional ex pression of the human atrial natriuretic peptide clearance receptor eDNA. Biochern. Biophys. Res. Cornrnun. 1 7 1 : 796-803 Porter, J. G. , Fuller, F., Schenk, D. B . , Arfsten, A . , Lewicki, 1 . A. 1988. Clon ing and expression of the receptor for atrial natriuretic peptide. See Ref. 57, pp. 4 1-44 Porter, J . G . , Wang, Y., Schwartz, K . , Arfsten, A . , Loffredo, A . , et al. 1988. Characterization of the atrial natriuretic peptide clearance receptor using a vacci nia virus expression vector. J. Bioi. Chern. 263 : 1 8827-33

89. Quirion, R ., Dalpe, M . , Dam, T. V. 1986. Characterization and distribution of receptors for the atrial natriuretic pep tides in mammalian brain. Proc. Natl. Acad. Sci. USA 83: 1 74-78 90. Rashatwar, S. S . , Cornell, T. L. , Lin coln, T. M. 1987. Effects of 8-bromo cGMP on calcium levels in vascular smooth muscle cells: possible regulation of calcium ATPase by cGMP-dependent protein kinase. Proc. Natl. Acad. Sci. USA 83:5685-91 9 1 . Resink, T. J . , Scott Burden, T . , Baur, D . , lones, C. R . , Buhler, F. R. 1988. Atrial natriuretic peptide induces break down of phosphatidylinositol phosphates in cultured vascular smooth-muscle cells. Eur J. Biochern. 172:499-505 92. Rocha, A. S . , Kufo, L. H. 1 990. Atrial peptide and cGMP effects on NaCI transport in inner medullary collecting duct. Arn. J. Physiol. 259:F258-68 93 . Saavedra, J. M . , Correa, F. M . , Plunk ett, L. M . , Israel, A . , Kurihara, M . , Shigematsuo, K . 1986. Binding of an giotensin and atrial natriuretic peptide in brain of hypertensive rats. Nature 320: 785-60 94. Scarborough, R. M., McEnroe, G. A . , Arfsten, A., Kang, L. L., Schwartz, K . , Lewicki, I. A. 1 988. D-atnino acid-sub stituted atrial natriuretic peptide analogs reveal novel receptor recognition require ments. J. Bioi. Chern. 263: 168 1 8-22 95. Scarborough, R. M . , Schenk, D. B . , McEnroe, G . A . , Arfsten, A . , Kang, L . L . , et al. 1986. Truncated atrial natriure tic peptide analogs. Comparison be tween receptor binding and stimulation of cyclic GMP accumulation in cultured vascular smooth muscle cells. J. Bioi. Chern. 261 : 1 2900-64 96. Schenk, D. B . , Jolmson, L. K . , Schwartz, K . , Sista, H . , Scarborough, R. M . , Lewicki, I. A. 1985. Distinct atrial natriuretic factor receptor sites on cultured bovine aortic smooth muscle and endothelial cells. Biochem. Biophys. Res. Comrnun. 127:433-42 97. Schenk, D. B . , Phelps, M. N . , Porter, J. G . , Fuller, F. , Cordell, B. , Lewicki, J . A. 1987. Purification and subunit com position of atrial natriuretic peptide re ceptor. Proc. Natl. Acad. Sci. USA 84:1521-25 98. Schenk, D. B . , Phelps, M. N . , Porter, J . G . , Scarborough, R . M . , McEnroe, G . A . , Lewicki, J . A . 1985. Identification of the receptor for atrial natriuretic factor on cultured vascular cells . J. Bioi. Chern. 260 : 14887-90 99. Schiffrin, E. L . , Turgeon, A . , Tremb lay, J . , Des\ongchamps, M . 199 1 . .

ANF RECEPTORS


100.

101.

102.

Effects of ANP, angiotensin, vasopres sin , and endothelin on ANP receptors in cultured rat vascular smooth muscle 107. cells. Am. J. Physiol. 260:H58-65 Schulz, S . , Singh, S . , Bellet, R. A . , Singh, G . , Tubb, D. J . , e t al. 1989. The primary structure of a plasma membrane guanylate cyclase demonstrates diversity within this new receptor family. Cell 108. 58:1 155-62 Smits, G. I., McCraw, D. E. , Trapani, A. J. 1 990. Interactions of ANP and bradykinin during endopeptidase 24. 1 1 inhibition: renal effects. Am. J. Physiol. 258:FI417-24 Stephenson, S . L. , Kenny, A. J. 1987. The hydrolysis of alpha-human atrial natriuretic peptide by pig kidney micro villar membranes is initiated by en dopeptidase 24. 1 1 . Biochem. J 243: . 109� 1 83-87 Stokes, T. J. Jr., MacConkey, C. L . Jr. , Martin, K. J. 1986. Atriopeptin 'III in creases cGMP in glomeruli but not in proximal tubules of the dog kidney. Am. 1 10. J. Physiol. 250:F27-3 1 Suzuki, M., Almeida, F. A., Nussenz veig, D. R . , Sawyer, D . , Maack, T. 1987. Binding and functional effects of atrial natriuretic factor in isolated rat kidney. Am. J. Physiol. 253:F917-28 Takayanagi, R., Inagami, T., Snajdar, R. M . , Imada, T. , Tamura, M., Mis 1 1 1. ono, K. S. 1987. Two distinct forms of receptors for atrial natriuretic factor in bovine adrenocortical cells. Purification, ligand binding, and peptide mapping. J. Bioi. Chern. 262: 12104-13 1 12. Trapani, A. J., Smits, G. J., McGraw, D. E., Spear, K. L., Koepke, I. P., et al. 1989. Thiorphan, an inhibitor of en dopeptidase 24. 1 1 , potentiates the ..

103.

104.

105.

106.

27

natriuretic activity of atrial natriuretic peptide. J. Cardiovasc. Pharmacol. 14: 419-24 Tremblay, J . , Gerzer, R., Vinay, P., Pang, S. C . , Beliveau, R . , Hamet, P. 1985. The increase of cGMP by atrial natriuretic factor correlates with the dis tribution of particulate guanylate cyc lase. FEBS. Lett. 1 8 1 : 1 7-22 Tseng, Y.-C. L. , Lahiri, S . , Sellitti, D. F. , Burman, K. D., D'Avis, I. C . , War tofsky, L . 1990. Characterization by affinity cross-linking of a receptor for atrial natriuretic peptide in cultured hu man thyroid cells associated with reduc tions in both adenosine 3 ' ,5 ' monophosphate production and thyrog lobulin secretion. J. Clin. Endocrinol. Metab. 70:528-33 Vandlen, R. L. , Arcuri, K. E. , Napier, M. A. 1985. Identification of a receptor for atrial natriuretic factor in rabbit aorta membranes by affinity cross-linking. J. Bioi. Chern. 260:10889-92 Winquist, R. I., Faison, E. P. , Wald man, S. A., Schwartz, K. , Murad, F., Rapoport, R. M. 1984. Atrial natriuretic factor elicits an endothelium independent relaxation and activates par ticulate guanylate cyclase in vascular smooth muscle. Proc. Natl. Acad. Sci. USA 8 1 :7661-64 Yip, C. C . , Laing, L . P. , Flynn, T. G. 1985. Photoaffinity labeling of atrial natriuretic factor receptors of rat kidney cortex plasma membranes. J. Bioi. Chern. 260:8229-32 Zeidel, M. L . , Silva, P., Brenner, B . M . , Seifter, I. L . 1987. cGMP mediates effects of atrial peptides on medullary collecting duct cells. Am. J. Physiol. 252:F55 1-59

Vascular atrial natriuretic factor receptors in spontaneously hypertensive rats.

[Atrial natriuretic factor].

Atrial natriuretic factor.

Growth-regulatory properties of atrial natriuretic factor.

Therapeutic use of atrial natriuretic factor.

Renal effects of atrial natriuretic factor.

Mechanisms of atrial natriuretic factor-induced vasodilation.

Divergent regulation of atrial natriuretic factor receptors in high-output heart failure.

Ontogeny of atrial natriuretic factor receptors and cyclic GMP response in rabbit renal glomeruli.

Identification and localization of atrial natriuretic factor receptors in human spermatozoa.

Atrial natriuretic factor in experimental cirrhosis.

Atrial natriuretic factor and transmural pressures.

Atrial natriuretic factor and related peptide hormones.

Atrial natriuretic factor after orthotopic heart transplantation.

Atrial natriuretic factor in edematous disorders.

Atrial natriuretic factor release in cardiomyopathic hamsters.

Atrial natriuretic factor and cardiopulmonary bypass.

Characterisation of atrial natriuretic peptide receptors in bovine ventricular sarcolemma.

Atrial natriuretic peptide receptors in human endometrial stromal cells.

Determinants of coronary effects of atrial natriuretic factor in dogs.

Human pharmacokinetics of an analogue of atrial natriuretic factor.

Cardiac atrial natriuretic factor during evolution of congestive heart failure.

Binding and aggregation of pro-atrial natriuretic factor by calcium.

Dysregulation of atrial natriuretic factor in hypertension-prone man.