kinin receptors

Clinical Reviews in Allergy and Immunology �9 Copyright 1998 by Humana Press Inc. 1080-0549/98/385-401/$12.25

Kinin Receptors

Francois Marceau* and Dimcho R. Bachvarov

Centre Hospitalier Universitaire de Quebec, Centre de Recherche du Pavilion I'H6teI-Dieu de Qu6bec, Qu6bec, Canada G1R 2J6;

E-mail: [email protected]

Introduction The major, but not exclusive interface between the kallikrein-kinin

system and cellular functions is the action of bradykinin (BK) and related peptides (the kinins) on highly specific receptors expressed by definite cell types. Indeed kinins, positively charged peptides (see Table 1 for structure), influence tissues and cells essentially by stimulating membrane receptors. Pharmacologic investigations dating back to the late 1970s have resulted in a receptor classification (B1 and B2) that is now supported by extensive molecular biology findings, and has influenced advances in medicinal chemistry and clinical pharmacology. Among more recent developments, the discovery of allelic polymorphisms in the human kinin receptor genes allows a fresh approach in the understanding of the kinin role in inflammatory and renal disease.

Kinin Receptor Classification Initial structure-activity studies of BK-related peptides indicated

that all BK fragments were nearly inactive in the most popular pharmacologic assay systems (e.g., contractility of the guinea pig ileum, rat uterus, and hypotension in the rat (1). Lys-BK (kallidin) was approxi- mately equipotent to BK in these systems, and des-Argg-BK, inactive, thus indicating that arginine carboxypeptidases commonly termed kininase I represented one of the inactivation pathways of kinins (2). The first hint of the duality of kinin receptor molecule originated from the very atypical structure-activity relationship observed for the contractile effect of BK and its fragments in the isolated rabbit aorta (3). It

*Author to whom all correspondence and reprint requests should be addressed.

Clinical Reviews in Allergy and Immunology 385 Volume 16, 1998

�9

<

t~

o

U

U

m

o ~

0 0 o O 0 ~ , O 0

>~ o~

~ ~ .m - U .~ ~ 0~

% _o mmm~ mmb

- ~ ~

Z ~ W Z Z ~ W

�9

g

~ L~

p-.

m m

mm mm oo oo oo oo ~o ~o !I II

%

%%% %~

2 2 2 ; 2

%%% ~%

<<< <<

o ~ ~ m

Z m ~ Z m

i

z Z

Z r,m i

o 9

u , ,...~

%

8

4~

~,"a 0

0

>.,Q)

Clinical Reviews in Allergy and Immunology Volume 76, 1298

Kinin Receptors 387

was found that BK exhibited relatively little potency, whereas the fragment without the C-terminal arginine residue, des-Arg9-BK, was the most potent contractile agent in the tested series. Moreover, analogs such as [LeuS]-des-Arg9-BK, designed by analogy to angiotensin II receptor antagonists, were found to be competitive antagonists of all kinins on that preparation (3). Since this was the first type of receptor for BK defined by both an potency order of the agonists and specific sequence-related antagonists, the receptor type for BK-related peptides in the rabbit aorta was designated as the B1 type (4). Later, it was found that both Lys-BK (kallidin) and Lys-des-Arg9-BK (des-Arg~~ have greater affinity for BIRs than the homolog pair BK and des-Argg-BK (4). The only natural kinin sequence with a subnanomolar affinity for the human BIR is Lys-des-Argg-BK (5), a fact of particular significance, because it suggests BIRs are a component of the "tissue" kallikrein- kinin system, since tissue kallikrein preferentially generates Lys-BK from low-mol-wt kininogen. However, the BIR was initially defined in vitro, since the most prominent effects of kinins both in vivo and in vitro are not mediated by this receptor type in normal animals and humans. Demonstration of the upregulation of BIRs by tissue injury in several in vivo systems supported the physiopathologic importance of this pharmacologic entity (6; see Physiopathologic Importance of Kinin Receptor Regulation).

The prominent effects of BK on normal animals (hemodynamic, algesic, proinflammatory) and on contractile tissues (e.g., the guinea pig ileum, the rat uterus) are currently known to be mediated by the B2 receptor type, a pharmacologic entity defined in 1985 when the first selective and competitive antagonists modeled on [D-PheY]-BK were produced (7). Some B2 receptor antagonists of particular importance are presented in Table 1. The drug development effort has been more sys- tematic for B2Rs than for BIRs, certainly reflecting the more impressive effects of native kinins (BK and Lys-BK) than that of their des-Arg 9- fragments in experimental systems based on normal animals and humans. An orally active, nonpeptide B2R antagonists of great potency and selectivity, FR 173657, has been recently reported (8; Table 1), introducing a qualitative step toward the clinical use of such a novel class of drugs.

Binding assays represent an important pharmacologic approach for kinin receptor studies (Table 2). The original binding assay for B2 receptors involved [3H]BK (9), which is still the most popular ligand. Physio- logical sodium or divalent cation concentrations severely reduced the binding of the ligand to the B2R present in membranes prepared from various organs and species, a distinctive feature of this system of rather obscure significance, but real practical importance in this assay (9). [3H]Lys-des-Arg9-BK has had the most widespread use as a BIR ligand


2

.=. M

o

r j

crj

2

2 ..4

=_. -~ 7~'-= ,~ .._- = C#.~

~ ~ .._- ~ = "~'-~.

LO "---~

.2 ~ ~

> ~ ' ~ p__.

. ~ ~ ~" ~ : ~ �9 N ~ ; _ ~ ~

,-~ ~ - ~ .~

�9 ~ ~ . ~

.~ . ~ -.~ . ~

I ~ o N?

o "5 ~ ~

< ~ : ~

~ o

--~ .~ "_~

~ ~ 0 0 ~

-= .~ ~ ~ ".~ ~ ~ -

~3

~ ~ or - - . ~ - ~ ,.~

o = ~ ~

< <

G)

~ 0

•

0 m m

~ 0 c ' 4 ~

o �9

u u

o.; D~ 3 o

Z

U:


Kinin Receptors 389

(reviewed elsewhere, 6). The antagonist [3H]Lys-[Leu8]des-Arg9-BK was used in another recent study (10). Based on the current understanding of the structure-activity relationships for both receptor types, these ligands are highly selective and, as natural sequences, possess the highest possible affinity for their respective receptor.

General Pharmacology of Kinins Kinins are potent (subnanomolar), short-lived (30 s or less ) mediators.

Exogenous BK injected in human or animal tissues reproduces the four classical cardinal signs of inflammation: redness, local heat, swelling, and pain (11). The identity of the major target cell types for kinins explains this profile: the redness and local heat may be determined by local endothelium-dependent vasodilation. The stimulation of endothelial cells also results in increased microvascular permeability, contributing to the exu- dation of protein rich fluid from the circulation (swelling). BK contracts several types of smooth muscle preparations, such as small human bronchi (12) and strips of human urinary bladder (13). Various other cell types are more or less influenced by kinins (enterocytes, fibroblasts, striated muscle), but the medical importance of these observations is not always clear. Nonmyelinated afferent neurons also possess receptors for kinins, explain- ing the ability of this simple peptide to produce pain and autonomous nervous system responses directly (14). Leukocytes may not be important target cells for kinins, at least in humans (11). Potentially important renal effects of kinins will be mentioned below.

Most circulatory effects of BK-related peptides are determined by the stimulation of endothelial cells from which secondary mediators are released to affect the vascular smooth muscle. The discovery of endothelium-derived relaxing factor (EDRF) was soon followed by the demonstration of its release by a variety of agonists, including BK (15). EDRF, now identified as nitric oxide (NO), is metabolically derived from L-arginine by a calcium-regulated cytosolic enzyme located in the endothelial cells. Endothel ium-dependent relaxation is a prominent mode for BK action in isolated blood vessels, such as the human pulmo- nary and coronary arteries (16,17). The BK-induced endothelial production of NO and subsequent rise of cyclic GMP in the vascular smooth muscle cells have been documented in bovine intrapulmonary arteries (18). A component of the vasorelaxation in this system is also mediated by prostaglandin 12 (prostacyclin), which is another secondary mediator frequently released by kinins from the endothelium and which stimu- lates cyclic AMP production in the smooth muscle cell (18). Prostanoid formation also occurs in other cell types possessing receptors for BK (12), probably via the cytosolic Ca 2§ sensitive phospholipase A 2. Other mecha- nisms of endothelial-dependent vasorelaxation are also suspected, such as endothel ium-dependent hyperpolarization of smooth muscle cells


390 Marceau and Bachvarov

(19), which probably represents the major mechanism for BK-induced relaxation of human isolated coronary arteries (17).

Both B1 and B2Rs are coupled to G proteins, predominant ly the pertussis toxin-insensi t ive G type, which are p r imar i ly l inked to

�9 �9 �9 q . . . . . .

phosphohpase C-/3 actwatlon, with lntracellular calcium moblhzat lon by inositol 1,4,5-tr iphosphate and add i t iona l in t race l lu lar effects (10,20-22)�9

Physiopathological Importance of Kinin Receptor Regulation

Although essentially all the pharmacological actions of kinins listed above depend on B2Rs, it is becoming increasingly clear that BIR may amplify the effects of B-2Rs as a function of time during inflammatory conditions, sepsis or other forms of tissue injury (e.g., the isolation and in vitro incubation of smooth muscle preparations). The responses usually are qualitatively similar effects to those mediated by the B2Rs in the same cell types. This may be a result of cytokine-regulated de novo formation of the BIR driven by a transcriptional activation of the corresponding gene (6,23). Thus, a time- and protein synthesis-dependent induction of BIRs has been verified in recent articles utilizing vascular endothelial cells (isolated human coronary artery; 24), human vascular or nonvascular smooth muscle cells (25,26), rat colonocytes (27), and sensory neurons from rodents (28). Recently the kinin receptor status in normal and inf lamed h u m a n pyloric gastric mucosa has been esti- mated by immunohis tochemica l studies (29). Control an t rum tissue showed s t rong immunoreac t iv i ty for B-2Rs wi th pos i t iv i ty noted along the luminar border, at the base of the mucous and stem cells, and there was no BIR immunolocal izat ion. However , biopsies from pat ients wi th gastritis showed a decrease in immunolabe l ing of the B2Rs and an induct ion of the BIRs, especial ly in regenera t ing epi- thelial cells. This first s tudy of the ident if icat ion of k inin receptors on gastric mucosal cells indicates a possible role for k in in BIRs in gastritis. The upregula t ion of BIRs by tissue in jury may explain several observat ions of in vivo enhanced funct ional responses to the corresponding agonists in systems per ta in ing to h e m o d y n a m i c s and pain percept ion (30,31)�9 All these systems expressed a pre-exis tent popula t ion of B2Rs, but acquired a popula t ion of BIRs as a funct ion of t reatments that can be at t r ibuted to tissue injury. Exposure to exogenous in ter leukin 1 (IL-1), a powerful in f l ammatory cytokine, is active as a BIR inducer (6,28,31). Recent observat ions indicate that mi togen activate protein (MAP) kineses may media te the effect of cytokines and tissue in jury on BIR gene express ion (32). Little is known about the t ranscr ipt ional regula t ion of the B2R, but there is


Kinin Receptors 391

l imited evidence that this gene is responsive to the physio logica l mil ieu (Table 3).

Molecular Biology of Kinin Receptors The era of the study of kinin receptors using methods of molecular

biology began in 1991 with the expression cloning of the rat B2R (36) (Table 3); the BIR of human origin, was later defined at the cDNA level in 1994 (5). Figure 1 shows the pr imary structure of both human kinin receptors al igned for maximal homology. A BK receptor has been cloned from rat uterus, using a Xenopus oocyte expression assay and shown to have the pharmacological profile of a B2R (33). Subsequently, highly homologous B2Rs have been cloned and sequenced from human and other animal species (Table 3), the corresponding multiexon human gene was cloned, and its localization has been mapped to chromosome 14 (34-37). Sites of possible functional significance are conserved in all four species studied (three N-linked glycosylation sites, a palmitoyla- tion site, several phosphorylat ion sites; 38). Recently, a putative model of BK bound to the rat B2 receptor has been generated (39). The model emphasizes the importance of negatively charged residues in extracellular loop 3 of the receptor (most notably Asp 268 and Asp 286) in the binding of the N-terminal part of BK. A hydrophobic pocket, composed of residues Leu TM, Val ~~ Ile 112 and Phe 261 is also postulated to interact wi th the C-terminal part of the BK molecule that forms a B-turn. Mutagen- esis experiments describing mutations that result in both a loss of BK affinity as well as those who have no effect on BK affinity are in good agreement with the proposed structure. The amino acid residues postulated to interact with BK are well conserved in B2R genes studied thus far in four different species (38).

It has been known for a long time that the human embryonic cell line IMR-90 expresses B-1Rs, and stimulation leads to metabolic effects, such as collagen and DNA synthesis (40). Menke et al. (5) mention (with few details) that these cells bind [3H]Lys-des-Argg-BK and that the binding is vigorously upregulated by pretreating the cells with IL-113. These st imulated cells were an enriched source of mRNA util ized for the expression cloning of the human B-1R cDNA (5). Different mol-wt mRNA fractions were consecutively injected in Xenopus laevis oocytes, and the photoprote in aequorin was utilized as an indicator of the ability of the BIR agonist Lys-des-Arg9-BK (des-Argl~ to medi- ate Ca 2§ mobil izat ion in the injected oocytes. A 1307-bp clone that included a 1059 nucleotide open reading frame encoding a 353 amino acid protein was thus isolated and proposed to encode the BIR (5). The predicted sequence turned out to be 36% identical with the human B2R, its closest relative. The cloned BIR exhibited the seven-transmem- brane domains typical of G-protein-coupled receptors and three poten-


2

.=.

�9

-m

.9

m.

~n

m

o

o

m. <

o= ~-~ ".~ o

~.~ ~ " ~

t ' - .

.~" " ~ ~ . ~ . ~

~9

�9 "m

4~

eq ,.~

~ ~ o ~

�9 ~ ~ { ~

~ ~ --- .~ = ~

o

m

2

L~ ~

<~

E ~ .~ o .o

~ m

G;

m

0 0~ 0

0 9 ~ ~a

�9 �9 U

L9 <


~ ~ ~.~. ~ - ~ o ~

~-~ ~ ~.~

~ o ~ .-~ ~ . ~~ ~ ~ ~= ~

~ ~ . ~ ~. -

. ~

~ o~ ~ ~ o o

< ~ <

o I--t r/3

o

" 0

.=

U c ~

o

�9 ~ r ~

~:~ �9 ~

o

�9

o

2

~.~

~'~


394

hu B2R a

h u B~R b

Marceau and Bachvarov

MLNVTLQGPTLNGTFAQSI<Cp... QVEWLGWLNTIQPPFLWVLFVLATLENTF

[I ~ I 1 ~ i F I I I MASS WP PLELQ S SNQS QL FPQNATACDNAPEAWDLLHRVLPTF I I S I CFFGLLGNLF

TM 1

50

57

VLSVFCLHKSSCTVAEIYLGNLAAADLILACGLPFWAITISNNFDWLFGE

II II I llIlil IIli II lllIli I I I I II VLLVFLLPRRQLNVAEIYL.A-NLAASDLVFVLGLPFWAENIWNQFNWPFGA

TM-2

i00

107

TLCRVI/NAIISMNLYSSICFLMLVSIDRYLALVKTMSMGRMRGVRWAKLY

II;i I I! II I !If li I II I I LLCRVINGVIKA/qLFISIFLWAISQDRYRVLVHPMASGRQQRRRQARVT

TM-3

150

] 57

SLVIWGCTLLLSS PMLVFRTMKEYSDEGIiNVTACVISYPSLIWEVF'FN~L

~! IFlr I I i!ll I ! CVI,IW~/VGGLLSIPTFLLRSIQAVPD..LNITACZLLLPHEAWHFARIVE

TM-4

20O

205

I,NMZ/GFLLPLSVITFCTMQIMQVLRNNEMQKFK..EIQTERRATVLVLVVLL

il IJilIl i i l II 1 I i i LNILGFLLPLAAIVFFNYHILASLRTREEVSRTRVRGPKDSKTTALILTLVV

TM-5

250

257

LFIICWI,PFQZSTFLDTLHRLGILSSCQDERIIDVITQIASFIVlAYSNSCL

I rl I JJ [ ~ I ii P I i ! J] I AFLVCWAPYHFFAFLEFLFQVQAVRGCFWEDFIDLGLQLANFFAFTNSSL

TM 6 TM 7

300

307

NPL\ryvIVGKRFRKKSWEVYQGVCQKGGCRSE P ! QMENSMGTLRTS I SVERQ IHKLQDWAGSRQ 364

!i II II dl IIr I J NPVITgFVGRLFRTKVWELYKQCTPKSLAPISSSHRKEIFQLFWRN 353

Fig. 1. Consensus predicted structure of the human BK B2 and B1 receptors. From GenBank sequences M88714 and U12512. qn the B2R cDNA in-frame start codons upstream the presented deduced sequence suggest that the N-terminal domain could be extended by up to 27 residues (94). ~Sequence variants for human B1 are reported: R ~" (10), R 24~,, and S 2~'~ (GenBank sequence U22346).

tial sites of N-glycosylation. Two conserved Cys residues that are proposed to form a disulfide bond be tween the second and third extracellular domains in nearly all G-protein-coupled receptors were also present in this sequence. Potential phosphoryla t ion sites for protein kinase C and cAMP-dependent protein kinase were found in intracel- lular domains 2 and 3, and the carboxyl-terminal domain. Similar phosphorylat ion sites in other G-protein-coupled receptors have been implicated in short-term desensitization of the receptor following agonist st imulation. Binding compet i t ion studies pe r fo rmed on either IMR-90 cells or COS-7 cells transfected with an expression vector con- taining the cloned sequence showed structure-activity relationships that are generally similar to that observed in rabbit cells, except for a


Kinin Receptors 395

low relative affinity of des-Arg9-BK. The latter peptide is about seven times less potent than Lys-BK and about 2000-fold less potent than cold Lysdes-Argg-BK to compete for [3H]Lys-des-Arg9-BK binding on the human receptor. The BIR antagonist Lys-[LeuS]des-Arg9-BK effectively displaced 3H-labeled Lys-des-Arg9-BK from the cloned receptor, whereas the B-2R antagonist Hoe-140 did not, which indicates that the expressed receptor had the pharmacological characteristics of the B1R subtype. The structure and the genomic organization of the human BIR gene were determined (41,42), and indicate that this receptor contains three exons separated by two introns. The first and the second exon are noncoding, but the coding region and the 3'-flanking region are located entirely within the third exon. Preliminary studies demonstrate that the region located at a 5'-position relative to exon i bears the features of a comparatively strong inducible promoter with a functional TATA box (42; Bachvarov et al., in preparation). Numerous potential transcrip- tion factor binding sites are located in this region, notably seven AP-1 binding motifs, and current functional analysis of the region has the potential to elucidate the cytokine and MAP kinase regulation of the expression of the BIR. The human BIR gene has been assigned to chromosome 14q32, at a close site relative to the B2R gene (43,44).

The molecular definition of both types of kinin receptors allowed studies of considerable academic and practical interest for the better understanding; of the role of the kallikrein-kinin system in health and disease. Binding and second messenger studies based on cloned receptors expressed under controlled conditions in mammalian cells devoid of kinin receptors offer unambiguous pharmacologic evidence regarding receptor identity (10,20-22). Notably, this approach has permitted assignment of significant pharmacologic variations from one preparation to the other explicable by species differences in both the B1 and B2 receptor types, without evidence for other genetically determined receptor subtypes within each species (21,38,45). Muta- genesis and chimera construction have been used to define better the structure-function relationships, primarily for the B2R (46-52). Thus, the docking of B2R agonists, antagonists, the sensitivity to sodium ions, and the post-stimulation internalization behavior have been shown to involve specific parts of the molecule (Table 3). Knowledge of the peptide sequence of the receptors allowed investigators to raise antireceptor antibodies with original applications, such as definition of ligand docking in extracellular domains, and receptor detection in normal and pathologic tissue sections (29,53,54; Table 3).

An additional application derived from the genetic definition of the kinin receptors involves gene inactivation by homologous recom- bination (gene "knockout") in mice, since the B2R gene knockout mouse has been recently produced (55). Although it is phenotypically normal,



it exhibits severe hypertension with end-organ damage when exposed to an excess of dietary NaC1 (56), thus confirming the suspected natri- uretic and renal role of the kallikrein-kinin system. The BIR gene knockout is not yet reported, but we know that cytokine regulation of the BIR gene expression is not disrupted in B2R knockout mice (28).

The study of the human gene corresponding to both types of kinin receptors has revealed allelic polymorphisms (Table 3), some of which may be of clinical significance. An exon 1 polymorphism of apparent clinical significance has been described very recently for the B2R gene (57): alleles differ by a 9-bp deletion, designated (-) vs the complete sequence, designated (+). The (-) allele, presumably more stable relative to the action of RNases, seems to be somewhat overexpressed and is always present in the most symptomatic cases of C1 inhibitor deficiency (hereditary angioedema with angioedema crises). Thus, the B2R (-) allele is proposed to modulate in a dominant manner the phenotype (penetrance) of the basic genetic defect in this disorder, the C1 inhibitor deficiency, which leads to an increased effect of plasma kallikrein activity. Other polymorphisms of the B2R gene have been described, but have not yet been linked to clinical conditions (Table 3). Recently, two BIR gene polymorphisms were characterized in our laboratory (44). The frequencies of the two found allele pairs were determined in healthy volunteers and in patients with a history of end stage renal failure. An A1~ polymorphism has been identified in exon 3 in a minority of volunteer blood donors, which is located 35 nucleotides downstream from the stop codon and 14 nucleotides upstream from the polyadenylation signal; it appeared to be clinically neutral. A second and more frequent polymorphism consists of a single base substitution (G--699----~C) in a positive control region of the promoter. This polymorphism is significantly less frequent in the popula- tion of renal failure patients and determines an increased activity of the promoter function in constructions involving a reporter gene (44). The altered prevalence of this allele was also found in most etiologic sub- groups of uremic patients. Thus, the polymorphism of the BIR promoter may be a marker of prognostic significance for the preservation of renal function in diseased individuals. The hypothet ical influence of the relative BIR overexpression determined by the C allele could not be linked to a specific etiology, but may rather be related to nonspecific compensatory mechanism(s), like resistance to ischemic damage, main- tenance of glomerular filtration, and so forth.

Therapeutic Applications of Drugs Affecting Kinin Receptors

Clinical applications currently under investigation for B2R antagonists are based on their possible anti-inflammatory effects in res- Clinical Reviews in Allergy and Immunology Volume 16, 1998

Kinin Receptors 397

piratory allergies, polytrauma, and brain edema (58-60; Table 2). Con- versely, a B2R agonist resistant to angiotensin I converting enzyme (ACE) degradation, RMP-7 (Table 1), is under s tudy to open the b lood- brain barrier as an adjuvant to cancer chemotherapy (61). This is a deliberate use of the inflammatory pharmacologic profile of BK Animal studies suggest that BIR antagonists have an interesting analgesic effect in the later phases of inflammatory models (62,63); this analgesic effect has been qualified as peripheral, not prone to tolerance, and not associ- ated wi th physical dependence (63). In the latter s tudy, Hoe 140 was not active, al though some analgesic effect of B2R can be demonstrated in acute inflammation (14,62). Anti-inflammatory effects of kinin receptor antagonists have been also demonstrated in various animal models (Table 3).

Few cardiovascular drug classes have been more successful than ACE inhibitors in the last 15 years. Such drugs as captopril, enalapril, and several others have been clinically shown to exert beneficial effects in patients with high blood pressure, cardiac hypertrophy, congestive heart failure, and diabetic nephropathy (64). However, the mode of action of ACE inhibitors is not totally clear. ACE (kininase II) is a metal- lopeptidase that can accept with high affinity a variety of substrates in addit ion to angiotensin I, including BK and des-Arg9-BK, which are inactivated by this enzyme. There is a persistent suggestion in the literature that at least a part of the beneficial and side effects of ACE inhibitors is derived from the potentiation of endogenous BK, and kinin receptor antagonists have been exploited to s tudy this question in animals (64). The role of BK in the therapeutic effects of ACE inhibitors is very dependent on the model in animal studies, likely to be modest in essential hypertension, but perhaps substantial in nephrovascular hyper tens ion. The kal l ikre in-kinin system may not be active to a significant degree in normal individuals, but rather recruited in tissue injury situations (i.e., ischemia; 65) or by specific physiological conditions (such as high-sodium intake). The role of BK in some inflammatory/anaphylactoid side effects of ACE inhibitors is not firmly established, but possible, since icatibant prevents captopril-induced cough in animals or extracorporeal circulation-induced anaphylactoid reaction in humans under ACE inhibitor therapy (66,67).

Summary Rapid developments are expected in the molecular pharmacology

of both B1, and B2 types of kinin receptors, since the underlying genetic structures are now known and widely studied. The consequences of kinin receptor duality and physiopathological regulation have not yet been fully appreciated. Medicinal chemistry is also an active front of



research in kinin pharmacology, as more effective drugs targeted at kinin receptors are regularly reported. Various complementary molecular approaches (the receptor binding, cloning, immunoreacting, mutagenesis, inactivation, the study of regulation, allelic polymorphisms, and so forth) are expanding our knowledge of the role of kinins in allergy, inflammation, and singularly, renal medicine.

Acknowledgments Work from the authors' laboratory was supported by the Medical

Research Council of Canada (grant MT-14077), the Kidney Foundation, of Canada, the Quebec Heart & Stroke Foundation and Laboratories Fournier S. A. (France). D. R. B. is the recipient of the E. J. B. Tomlinson Scholarship Award from the Kidney Foundation of Canada.

References 1. Stewart, J. M. (1979), Handbook Exp. Pharmacol. vol. 25 (suppl.), Erd6s, E. G.,

eds., Springer, New, York, pp. 227-272. 2. Erd6s, K. G. and Sloane, E. M. (1962), Biochem. Pharmacol. 11, 585-592. 3. Regoli, D., Barabe, J., and Park, W. K. (1977), Can. J. Physiol. Pharmacol. 55, 855-867. 4. Regoli, D. and Barabe, J. (1980), Pharmacol. Rev. 32, 1-46. 5. Menke, J. G., Borkowski, J. A., Bierilo, K. K., MacNeil, T., Derrick, A. W.,

Schneck, K. A., et al. (1994), J. Biol. Chem. 269, 21,583-21,586. 6. Marceau, F. (1985), lmmunopharmacology. 30, 1-26. 7. Vavrek, R. J. and Stewart, J. M. Peptides 6, 161-164. 8. Aramori, I., Zenkoh, J., Morikawa, N., O'Donnell, N., Asano, M., Nakamura,

K., et al. (1997), Mol. Pharmacol. 51, 171-176 9. Innis, R. B., Manning, D. C., Stewart, J. M, and Snyder, S. H. (1981), Proc. Natl.

Acad. Sci. USA 78, 2630-2634. 10. Bastian, S., Loillier, B., Paquet, J. L., and Pruneau, D. (1997), Br. J. Pharmacol.

122, 393-399. 11. Marceau, F., Lussier, A., Regoli, D., and Giroud, J. P. (1983), Gen. Pharmacol.

14, 209-229. 12. Molimard, M., Martin., C. A. E., Naline, E., Hirsch, A., and Advenier, C. (1995),

Eur. J. Pharmacol. 278, 49-54 13. Andersson, K. E., Hedlund, H., and Stahl, M. (1992), Acta. Physiol. Scand.

145, 253-259 14. Steranka, L. R., Manning, D. C., DeHaas, C. J., Ferkany, J. W., Borosky, S. A.,

Connor, J. R., et al. (1988), Proc. Natl. Acad. Sci. USA 85, 3245-3249. 15. Furchgott, R. F. (1983), Circ. Res. 53, 557-573. 16. Feletou, M., Martin, C. A. E., Molimard, M., Naline, E., Germain, M., Thurieau,

C., et al. (1995), Eur. J. Pharmacol. 274, 57-64. 17. Nakasima, M., Mombouli, J. V., Taylor, A. A., and Vanhoutte, P. M. (1993), J.

Clin. Invest. 92, 2867-2871. 18. Ignarro, L. J., Byrns, R. E., Buga, G. M., and Wood, K. S. (1987), Am. J. Physiol.

253, H1074-H1082. 19. Mombouli, J. V. and Vanhoutte, P. M. (1995), Annu. Rev. Pharmacol. Toxicol.

35, 679-705. 20. Austin, C. E., Faussner, A., Robinson, H. E., Chakravarty, S., Kyle, D. J., Bathon,

J. M., et al. (1997), J. Biol. Chem. 272, 11,420-11,425.


K i n i n Receptors 3 9 9

21.

22.

23.

24. 25.

26.

27. 28.

29.

30.

31. 32.

33.

34.

35.

36.

37.

38.

39.

40. 41.

42. 43.

44.

45.

46.

47.

48.

49.

Clinical Reviews in Allergy and Immunology

Hess, J. F., Borkowski, J. A., MacNeil, T., Stonesifer, G. Y., Fraher, J., Strader, C. D., et al. (1994), Mol. Pharmacol. 45, 1-8. De Weerd, W. F. C. and Leeb-Lundberg, L. M. F. (1997), J. Biol. Chem. 272,17,858- 17,866. Marceau, F., Larriv6e, J-F., Saint-Jacques, E., and Backvarov, D. R. (1997), Can. J. Physiol. Pharmacol. 75, 725-730. Drummonds, G. R. and Cocks, T. M. (1995), Br. J. Pharmacol. 116, 3083-3085. Sardi, S. P., Perei, H., Antunez, P., and Rothlin, R. P. (1997), Eur. J. Pharmacol. 321, 33-38. Zuzack, J. S., Burkard, M. R., Cuadrado, D., Greer, R. A., Selig, W. M., and Whalley, E. T. (1996), J. Pharmacol. Exp. Ther. 277, 1337-1343. Teater, S. and Cuthbert, A. W. (1997), Br. J. Pharmacol. 121, 1005-1011. Seabrook, G. R., Bowery, B. J., Heavens, R., Brown, N., Ford, H., Sirinathsinghi, D. J. S., et al. (1997), Neuropharmacology 36, 1009-1017. Bhoola, R., Ramsaroop, R., Naidoo, S., Muller-Esterl, W., and Bhoola, K. D. (1997), Immunopharmacology 36, 161-165. Audet , R., Rioux, F., Drapeau, G., and Marceau, F. (1997), J. Pharmacol. Exp. Ther. 280, 6-15. Davis, A. J. and Perkins, M. N. (1994), Br. J. Pharmacol. 113, 63-68. Larriv6e, J-F., Bachvarov, D. R., Houle, F., Landry, J., Huot, J., and Marceau, F. (1998), J. Immunol., 160, 1419-1426. McEachern, A. E., Shelton, E. R., Bhakta, S., Obernolte, R., Bach, C., Zuppan, P., et al. (1991), Proc. Natl. Acad. Sci. USA 88, 7724-7728. Eggerickx, D. E., Raspe, E., Bertrand, D., Vassart, G., and Parmentier, M. (1992), Biochem. Biophys. Res. Commun. 187, 1306-1313. Powell, S. J., Slynn, G., Thomas, C., Hopkins, B., Briggs, I., and Graham, A. (1993), Genomics 15, 435-438. Ma, J. X., Wang, D. Z., Ward, D. C., Chen, L., Dessai, T., and Chao, J. (1994), Genomics 23, 362-369. Kammerer, S., Braun, A., Arnold, N., and Roscher, A. A. (1995), Biochem. Biophys. Res. Comm. 211, 226-233. Bachvarov, D. R., Saint-Jacques, E., Larriv6e, J. F., Levesque, L., Rioux, F., Drapeau, G., et al. (1995), ]. Pharmacol. Exp. Ther. 275, 1623-1630. Kyle, D. J., Chakravarty, S., Sinsko, J. A., and Storman, T. M. (1994), J. Med. Chem. 37, 1347-1354. Goldstein, R. H. and Wall, M. (1984), ]. Biol. Chem. 259, 9263-9268. Bachvarov, D., Hess, J. F., Menke, J. G., Larriv6e, J-F., and Marceau, F. (1996), Genomics 33, 374-381. Yang, X. and Polgar, P. (1996), Biochem. Biophys. Res. Comm. 222, 718-725. Chai, K. X., Ni, A., Wang, D., Ward, D. C., Chao, J., and Chao, L. (1996), Genomics 31, 51-57. Bachvarov, D. R., Landry, M., Pelletier, I., Chevrette, M., Betard, C., Houde, I., et al. (1998), J. Am. Soc. Nephrol. 9, 598-604. Hess, J. F., Derrick, A. W., MacNeil, T., and Borkowski, J. A. (1996), Immuno- pharmacology 33, 1-8. Leeb, T., Mathis, S. A., and Leeb-Lundberg, L. M. F. (1997), J. Biol. Chem. 272, 311-317. Fathy, D. B., Mathis, S. A., Leeb, T., and Leen-Lundberg, L. M. F, (1997), FASEB. J. 11, A1328, (Abstract). Quitterer, U., Abdalla, S., Jarnagin, K., and Muller-Esterl, W. (1996), Biochem. 35, 13,368-13,377. Novotny, E. A., Bednar, D. L., Connolly, M. A., Connor, J. R., and Stormann, T. M. (1994), Biochem. Biophys. Res. Comm. 201, 523-530.

Volume 16, 1998


50. 51. 52.

53,

54.

55.

56.

57.

58.

59.

60.

61.

62. 63. 64. 65. 66.

67. 68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

Clinical Reviews in Allergy and Immunology

Prado, G. N., Taylor, L., and Polgar, P. (1997), J. Biol. Chem. 272, 14,638-14,642. Nardone, J. and Hogan, P. G. (1994), Proc. Natl. Acad. Sci. USA 91, 4417-4421. Jarnagin, K., Bhakta, S., Zuppan, P., Yee, C., Ho, T., and Phan, T., et al. (1996), J. Biol. Chem. 271, 28,277-28,286. Alla, S. A., Quitterer, U., Grigoriev, S., Maidhof, A., Haasemann, M., Jarnagin, K., et al. (1996), J. Biol. Chem. 271, 1748-1755. Raidoo, D. M., Ramsaroop, R., Naidoo, S., Muller-Esterl, W., and Bhoola, K. D. (1997), Immunopharmacology 36, 153-160. Borkowski, J. A., Ransom, R. W., Seabrook, G. R., Trumbauer, M., Chen, H., Hill, R. G., et al. (1995), J. Biol. Chem. 270, 13,706-13,710. Alfie, M. E., Yang, X. P., Hess, F., and Carretero, O. A. (1996), Biochem. Biophys. Res. Comm. 224, 625-630. Lung, C. C., Chan, E. K. L., and Zuraw, B. L. (1997), J. Allergy. Clin. Immunol. 99, 134-146. Fein, A. M., Bernard, G. R., Criner, G. J., Fletcher, E. C., Good, J. T., Knaus, W. A. (1997), J. Am. Med. Assoc. 277, 482-487. Akbary, A. M., Wirth, K. J., and Scholkens, B. A. (1996), Immunopharmacology 33, 238-242. Austin, C. E., Foreman, J. C., and Scadding, G. K. (1994), Br. J. Pharmacol. 111, 969-971. Black, K. L., Cloughesy, T., Huang, S. C., Gobin, Y. P., Zhou, Y., Grous, J., et al. (1997), J. Neurosurg. 86, 603-609. Perkins, M. N., Campbell, E., and Dray, A. (1993), Pain 53, 191-197. Sufka, K. J. and Roach, J. T. (1996), Pain 66, 99-103. Marceau, F. (1997), Can. J. Cardiol. 13, 187-194. Gianella, E., Mochmann, H. C., and Levi, R. (1997), Circ. Res. 81, 415-422. Fox, A. J., Lalloo, U. G., Be|visi, M. G., Bernareggi, M., Chung, K. F., and Barnes, P.J. (1996), Nature Med. 2, 814-817. Davidson, D. C., Peart, I., Turner, S., and Sangster, M. (1994), Lancet 343, 1575. Gobeil, F., Pheng, L. H., Badini, I., Nguyen-Le, X. K., Pizard, A., Rizzi, A., et al. (1996), Br. J. Pharmacol. 118, 289-294. Gera, L., Stewart, J. M., Whalley, E. T., Burkard, M., and Zuzack, J. S. (1996), lmmunopharmacology 33, 183-185. Sawntz, D. G., Salvino, ]. M., Dolle, R. E., Casiano, F., Ward, S. J., Houck, W. T., et al. (1994), Proc. Natl. Acad. Sci. USA 91, 4693-4697. Levesque, L., Harvey, N., Rioux, F., Drapeau, G., and Marceau, F. (1995), Immunopharmacology 29, 141-147. Murone, C,, Perich, R. B., Schlawe, l., Chai, S. Y., Casley, D., Macgregor, D. P., et al. (1996), J. Pharmacol. 306, 237-247. Figueroa, C. D., Gonzalez, C. B., Grigoriev, S., Alla, S. A., Haaseman, M., Jarnagin, K., et al. (1995), J. Histochem. Cytochem. 43, 137-148. Blais, C., Couture, R., Drapeau, G., Colman, R. W., and Adam, A. (1997), Arthri- tis. Rheum. 40, 1327-1333. Feletou, M., Jamonneau, I., Germain, M., Thurieau, C., Fauchere, J. L., Villa, P., et al. (1996), J. Cardiovasc. Pharmacol. 27, 500-507. Relton, J. K., Beckley, V. E., Hanson, W. L., and Whallet, E. T. (1997), Stroke 28, 1430-1436. Mathis, S. A., Criscimagna, N. L., and Leeb-Lundberg, L. M. F. (1996), Mol. Pharmacol. 50, 128-139. Smith, J. A. M., Webb, C., Holford, J., and Burgess, G. M. (1995), Mol. Pharmacol. 47, 525-534. Blaukat, A., Abdalla, S., Lohse, M. J., and Muller-Esterl, W. (1996), J. Biol. Chem. 271, 32,366-32,374.

Volume 16, 1998

Kinin Receptors 401

80. Jong, Y. J. I., Dalemar, L. R., Wilhelm, B., and Baenziger, N. L. (1993), Proc. Natl. Acad. Sci. USA 90, 10,994-10,998.

81. Alla, S. A., Buschko, J., Quitterer, U., Maidhof, A., Haasemann, M., Breipohl, G., et al. (1993), J. Biol. Chem. 268, 17,277-17,285.

82. Ransom, R. W., Young, G. S., Schneck, K., and Goodman, C. B. (1992), Biochem Pharmacol. 43, 1823-1827.

83. MacNeil, T., Bierilo, K. K., Menke, G. H., and Hess, J. F. (1995), Biochem. Biophys. Acta. 1264, 223-228.

84. Pesquero, J. B., Pesquero, J. L., Oliveira, S. M., Roscher, A. A., Metzger, R., Ganten, D., et al. (1996), Biochem. Biophys. Res. Comm. 220, 219-225.

85. Hess, J. F., Borkowski, J. A., Young, G. S., Strader, C. D., and Ransom, R. W. (1992), Biochem. Biophys. Res. Comm. 184, 260-268

86. Pesquero, J. B., Lindsey, C. J., Zeh, K., Paiva, A. C. M., Ganten, D., and Bader, M. (1994), J. Biol. Chem. 269, 26,920-26,925.

87. Madeddu, P., Parpaglia, P. P., Glorioso, N., Chao, L., Chao., J. (1996), Hyperten- sion 28, 980-987.

88. Braun, A., Kammerer, S., Bohme, E., Muller, B., and Roscher, A. A. (1995), Biophys. Res. Comm. 211, 234-240.

89. Braun, A., Maier, E., Kammerer, S., Muller, B., Roscher, A. A. A. (1996), Hum. Genet. 97, 688-689.

90. Lagneux, C. and Ribuot, A.C. (1997), Br. J. Pharmacol. 121, 1045-1046. 91. Dixon, B. S., Sharma, R. V., and Dennis, M. J. (1996), J. Biol.Chem. 271, 13,324-

13,332. 92. Madeddu, P., Emanueli, C., Varoni, M. V., Demontis, M. P., Anania, V., Gorioso,

N., et al. (1997), Br. J. Pharmacol. 121, 1763-1769. 93. Schroeder, C., Beug, H., and Muller-Esterl, W. (1997), J. Biol. Chem. 272, 12,475-

12,481. 94. Alla, S. A., Quitterer, U., Schroder, C., Blaukat, A., Horstmeyer, A., Dedio, J., et

al. (1996), Immunopharmacoloy;y 33, 42-45.


kinin receptors

Documents