Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Bradykinin Receptors

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_232

Synonyms

 B1BKR;  B1R;  B2BKR;  B2R;  BDKRB1;  BDKRB2;  BKB1R;  BKB2R;  BKR1;  BKR2;  Kinin B1;  Kinin B2

Historical Background

A primary mediator of inflammation, the nonapeptide bradykinin (BK) is a pharmacologically active peptide of the kinin group released in tissues and circulation as a consequence of coagulation cascade activation, more specifically by the kininogen cleavage by kallikrein. The enzyme kallikrein was described in 1930 by Werle and Frey. It was the first component of the kallikrein-kinin system (KKS) discovered, followed by the identification of bradykinin (BK) by Rocha e Silva and colleagues in 1949. In 1970s Regoli and coworkers characterized molecularly the two subtypes of kinin receptors B1 and B2, based in their pharmacological and expression profiles differences (Fig. 1). These findings enabled the subsequent development of different agonists and antagonists for these receptors (Leeb-Lundberg et al. 2005). The genes encoding these receptors were cloned in 1990s and after that, animal models for the study of this system were generated: the B2 knockout mice (Borkowski et al. 1995), the B1 knockout mice (Pesquero et al. 2000), and the knockout mice for both kinin receptors (Cayla et al. 2002).
Bradykinin Receptors, Fig. 1

Kallikrein-kinin system

Structural Aspects

The BK receptors are typical G protein coupled receptor (GPCR), consisting of a single polypeptide chain that spans the membrane seven times, with the N-terminal domain being extracellular and the C-terminal domain being intracellular. These receptors are present in different species of mammals like human, monkey, rats, mice, rabbit, and others.

In humans both receptors, B1 and B2, are homologues preserving 36% of identity at the amino acid level (Leeb-Lundberg et al. 2005). These receptors are encoded by three-exon genes. B1 receptor gene is in tandem with the B2 receptor gene, located sequentially (5′ direction) separated by only 12 kb at cromossome 14q32 in humans. This composition can vary between species like the deletion of exon 2 in mice (Cayla et al. 2002).

Knockout animal models of each kinin receptor gene by homologous recombination have been done. The B2 receptor knockout mice are fertile, apparently healthy, and when smooth muscle or neurons of these mice are stimulated with bradykinin they failed to produce response (Borkowski et al. 1995). The B1 receptor knockout mice are healthy, fertile, normotensive, and they are analgesic in behavioral tests of chemical and thermal nociception (Pesquero et al. 2000). The generation of a knockout mouse of both receptors (B1B2−/−) was also done. Due to the fact that both genes are in close chromosomal position, B1B2−/− mice could not be obtained by simple breeding of the single knockout lines. The B1 receptor gene was inactivated in embryonic stem cells derived from B2-deficient animals. These animals are normotensive and protected from endotoxin-induced hypotension (Cayla et al. 2007). Recently, another model of double-knockout of kinin receptors was generated by complete deletion of the gene locus (Kakoki et al. 2010).

Pharmacological Aspects

Kinins are locally released from their origin molecules, the kininogens, as a result of limited proteolysis by a class of serine proteases called kallikreins. The metabolite generated is the nonapeptide bradykinin or a decapeptide, kallidin (Lys-BK). Kinins cleavage by the kininase II also named angiotensin converting enzyme (ACE) generates inactive metabolites terminating bradykinin activity. The action of carboxipeptidases on kinins generates des-Arg9-BK (DBK) or Lys-des-Arg9-BK (Lys-DBK). The B2 receptor has high affinity for the intact kinins, those generated by either plasma or tissue kallikreins, BK and Lys-BK, in all mammalian species. B1 receptor responds to different kinin metabolites, either DBK or Lys-DBK, generated by arginine carboxypeptidases, such as carboxypeptidase N and M. In humans, plasma kallikrein forms BK, whereas tissue kallikreins form kallidin. In rodents, both plasma and tissue kallikrein generate BK. Receptor affinity for agonist ligands: B2 receptor, BK ≈ Lys-BK >> des-Arg9-BK and Lys-des-Arg9-BK; B1 receptor, Lys-des-Arg9-BK > Lys-BK ≈ des-Arg9-BK >> BK (Leeb-Lundberg et al. 2005).

Peptide antagonists for the kinin B1 receptor were the first antagonists generated based on modifications of the agonist structure, such as [Leu8]des-Arg9-BK and Lys-[Leu8]des-Arg9-BK. The search for antagonists showed that the spatial orientation of the C-terminal region of the peptide molecule is critical for antagonism. Many antagonists the for B2 receptor have been generated. The most known peptide antagonist is the icatibant or HOE-140. Non-peptide ligands for the kinin receptors have been designed and are yet a great field of study, since peptides are generally poor drugs for oral bioavailability and brain penetration (Leeb-Lundberg et al. 2005).

Signaling Pathways

In different species both kinin receptors are identified as seven transmembrane G protein coupled receptor. Various signal transduction mechanisms have been described for kinins depending on the cellular type. BK or DBK stimulates B2 or B1 receptors, respectively. Through the phospholipase C pathway (by Gq activation), kinin signaling leads to inositol 3-phosphate (IP3) generation and intracellular calcium mobilization, whereas through the  phospholipase A2 pathway (activated through Gi or calcium-dependent mechanisms) it leads to arachidonic acid release, also by activating the endothelium nitric oxide synthase (eNOS) and producing nitric oxide (NO). B2 receptor has also been found to directly interact with other eNOS in a G protein-independent manner (Leeb-Lundberg et al. 2005).

BK also transiently promotes tyrosine phosphorylation of  MAP Kinases and activates a Janus-activated kinase/STAT (JAK-STAT) pathaway. This involves tyrosine phosphorylation of both the Janus-activated kinase family tyrosine kinase Tyk2 and STAT3 followed by STAT3 nuclear translocation. B2 activates multiple transcription factors that regulate the induction of several cytokines involved in tissue injury and inflammation as well as B1 receptor induction. Besides these classical pathways, IL-1β and  TNF-α can stimulate the expression of B1 and B2 receptors by pathways involving activation of  NF-κB and MAPKs. Although the B1 and B2 receptors seem to couple to similar cellular signal transduction pathways, the patterns of signaling are different (Leeb-Lundberg et al. 2005; Brechter et al. 2008).

B1 and B2 receptor form homodimers and these receptors were found to spontaneously heterodimerize. Heterodimerization was associated with a specific proteolytic degradation of the participating B2 receptor and an increase in both agonist-dependent and -independent signaling of the heterologous receptor complex. The existence of a B2 receptor and angiotensin receptor 1 (B2/AT1) heterodimeric complex may have implications for blood pressure. The B2/ACE interaction modulates ACE activity (Sabatini et al. 2008).

B2 receptor function is controlled by short-term mechanisms involving fast ligand dissociation, receptor desensitization and internalization, and, after long-term stimulation, downregulation of the receptor occurs. In contrast, B1 receptors elicit persistent responses and signaling that are subjected to very limited desensitization and receptor internalization with very slow ligand dissociation (Couture et al. 2001).

Kinins and Disease

The kallikrein-kinin system (KKS) is present in numerous pathologies and the role it plays may vary. It can maintain the danous state of disease or play a protective role, as summarized below in Table 1.
Bradykinin Receptors, Table 1

Kinin receptors’ presence in various diseases

Disease

Effect

Inflammation

Pro-inflammatorya

Pain

Hyperalgesiaa

Infection

BK increase:

Vascular leakage and vasodilationa

Arterial vasodilatationa

Imune system (autoimmune diseases)

Imune cells stimulation and regulationb

Bone (arthritis and periodontitis)

Stimulate bone resorptionc

Respiratory system (asthma and rhinitis)

Increase in the expression of kininsd

Neurological disease

 

Alzheimer

Improvement of cognitive deficitse

Epilepsy

Deleterious and protective effectse

Sclerosis

B1R increases blood–brain barrier permeabilityf

Kidney nephrophaty

Chemokine productiong

Macrophage accumulationg

Metabolism

 

Diabetes

Prevention of progression of insulin-dependent diabetesh

Obesity

B2 absence enhance senescence in micei

B1−/− mice are protect from diet-induced obesityj

Cardiovascular

Hypertrophyk

Cardiopathyk

Hypertensionk,l

Atherosclerosism

Liver

Attenuates fibrosis/hepatocellular damagen

Cancer

Tumor growthl

Angiogenesis stimulationl

aCouture et al. (2001)

bSchulze-Topphoff et al. (2009)

cBrechter et al. (2008)

dProud (1998)

eLemos et al. (2010)

fSchulze-Topphoff et al. (2009)

gKlein et al. (2010)

hKakoki et al. (2010)

iKakoki et al. (2006)

jMori et al. (2008)

kSharma (2003)

lLeeb-Lundberg et al. (2005)

mMerino et al. (2009)

nKouyoumdjian et al. (2005)

Generated during inflammation and tissue injury, bradykinin contributes to the initiation and maintenance of inflammation, to exciting and sensitizing sensory nerve fibers, thus producing pain as reviewed by Couture and coalleagues in 2001. Thus the B2 receptor is involved in acute inflammation, including increased vascular permeability, venoconstriction, arterial dilatation, and pain through the activation of sensory nerve terminals. This receptor has a limited role in the cellular component of the inflammatory response involving leukocyte recruitment within the microcirculation. The activation of B2 receptors in sensory neurons promotes hyperalgesia. Bradykinin can sensitize nociceptors following the release of prostaglandins, cytokines, and nitric oxide either from sensory neurones, endothelial and immune cells or fibroblasts in addition to its interaction with mast cell mediators. The blockade of B2 receptors located on sensory neurons may be responsible for the analgesic property of B2 receptor antagonists. The pro-inflammatory effects of B1 receptors include promotion of blood-borne leukocyte trafficking, edema and pain. B1 receptors are primarily involved in persistent inflammatory pain and are expressed in macrophages, fibroblasts, or endothelial cells, where they may be responsible for inflammation mediators releasing (prostaglandins, cytokines, and nitric oxide) that sensitize or activate the nociceptors.

Because of its multicellular location and the mode of persistent signaling mechanism, the B1 receptor is likely to exert a strategic role in inflammatory diseases, particularly those with an immune etiology (asthma, rheumatoid arthritis, multiple sclerosis, and diabetes). In addition to the pro-inflammatory effects of kinin receptors, B1 receptors may exert a protective effect in brain inflammatory diseases such as multiple sclerosis by reducing T-lymphocyte infiltration into the brain (Schulze-Topphoff et al. 2009).

Kinins exert influence on multiple players of the immune system (i.e., macrophages, dendritic cells, T and B lymphocytes). BK is capable of modulating the activation, proliferation, migration, and effector functions of immune cells. Kinin receptors seem to be important in autoimmune conditions, such as rheumatoid arthritis, lupus, and myasthenia gravis (Schulze-Topphoff et al. 2008).

Kinin receptors are present in osteoblasts, osteoclasts, and fibroblasts, linking the kallikrein-kinin system with rheumatoid arthritis, periodontitis, and bone resorption. They can stimulate bone resorption through prostaglandins. Kinin B1 and B2 receptors synergistically potentiate IL-1β and TNF-α-induced prostaglandin biosynthesis in osteoblasts by a mechanism involving increased levels of cycloxygenase-2 (Brechter et al. 2008).

Many studies have demonstrated increased kinin generation associated with asthma, allergic rhinitis, and during viral rhinitis (Proud 1998). The first studies began with the analysis of the presence of kinins after allergen stimulation in allergic subjects and absence of them in non-allergic subjects. The inflammatory infiltration and relation between kinins and the chronic phase of the disease were then observed. Kinins are also associated with the release of the mast cell granule constituents, histamine, and tryptase, major mediators of acute phase. The kinin concentration increase during asthma is associated with the augment in histamine and other inflammatory markers, including eicosanoids. The administration of bradykinin by nasal spray to the upper airways of normal, nonatopic subjects, or of asymptomatic atopic individuals has been shown to result in the dose-dependent induction of symptoms of nasal obstruction, modest rhinorrhea, nasal irritation, and sore throat, but not sneezing (Proud 1998).

Kinin receptors are involved with brain damage in different forms. They act in multiplus sclerosis, epilepsy, and Alzheimer’s disease. Kinin B2 receptor promotes survival and protects against brain injury by suppression of apoptosis and inflammation induced by ischemic stroke. In epilepsy, the kinin B2 receptor also plays a neuroprotector effect and the kinin B1 receptor plays a deleterious, pro-epileptogenic action in animal models (Leeb-Lundberg et al. 2005). Kinin receptors are involved in neurodegeneration and increase of amyloid-b concentration, associated with Alzheimer’s disease (Lemos et al. 2010). More recently it was shown that during the aging process, the B1 receptor could be involved in neurodegeneration and memory loss. Nevertheless, the B2 receptor is apparently acting as a neuroprotective factor (Lemos et al. 2010). In inflammatory brain disease, like sclerosis, kinin B1 receptors are important in limitating migration of lymphocytes through the central barrier and inflammation in the brain (Schulze-Topphoff et al. 2009).

Kinins receptors are present in the kidney and are involved with kidney disease, such as renal failure and nephropathy. Since kinin receptors are present in patients in end stage of renal failure, treatment with a B1 receptor antagonist reduces both glomerular and tubular lesions and improve renal function trough the reduction of renal chemokine expression and macrophage accumulation in glomerulonephritis (Klein et al. 2010). Genetic association between B1 receptor polymorphisms and end-stage renal failure have been reported, as the B2 receptor polymorphism is associated with diabetic nephropathy (Leeb-Lundberg et al. 2005).

Lack of B1 and B2 receptors exacerbates diabetic complications, enhances the nephropathy (glomerulonephritis), neuropathy (decrease the time of nervous impulse), and bone mineral loss caused by insulin-dependent diabetes in mice (Kakoki et al. 2010). The development of diabetic retinopathy increases vascular permeability, neovascularization, inflammation and B2 activation contributes to vascular permeability and edema, which suggests the correlations between the KKS and microvascular complications of diabetes. Studies performed in diabetic mice demonstrated that the absence of B2 receptor in these animals increases indicators of senescence like alopecia, skin atrophy, kyphosis, osteoporosis, testicular atrophy, lipofuscin accumulation in renal proximal tubule and testicular Leydig cells, and apoptosis in the testis and intestine (Kakoki et al. 2006).

The kinin B2 receptor agonist BK may participate in the regulation of substrate utilization by several tissues by improving blood flow and substrate delivery to the tissues and also by promoting translocation of glucose transporters. It appears to improve the release of insulin and improve insulin sensitivitiy. Furthermore, insulin may activate the kallikrein-kinin system, which consequently may increase its metabolic effects. However, in experimental diabetes mellitus, BK may participate in the inflammatory reaction leading to Langerhans islets destruction (Damas et al. 2004). Kinin B1 receptor is involved in obesity, as shown by Mori et al. The absence of B1 receptor in mice decreases plasma leptin levels, increases leptin sensibility, protects mice from diet-induced obesity (diet with 45% of fat), and augments energy expenditure.

The KKS has importante role in various pathological processes of the cardiovascular system, such as hypertension, cardiac failure, ischemia, left ventricular hypertrophy, and endotoxemia. There is activation of BK activity in endotoxemia. On the other hand, it seems that there is deficient activity of the KKS in hypertension, cardiac ischemia, and development of left ventricular hypertrophy. These pathological states might be due to a genetic abnormality of the KKS or downregulation of the BK receptors (Sharma 2003). Several studies have detected a significant association between the B2 receptor 58 C/T polymorphism and hypertension (Leeb-Lundberg et al. 2005). Kinin B1 receptor deficiency aggravates atherosclerosis and aortic aneurysms in mice under cholesterolemic conditions, supporting an antiatherogenic role for the kinin B1 receptor (Merino et al. 2009).

The KKS is also present in the liver and is related to liver disease. BK can induce portal hypertensive response when injected in the liver. This hepatic hypertensive response to BK is mediated by the B2 receptor and modulated by the L-Arg/nitric oxide pathway. There is also evidence of the participation of BK in the pathogenesis of vasodilatation and ascites formation in cirrhotic patients (Kouyoumdjian et al. 2005).

Finally, the ability of BK to stimulate vessel growth and increase vascular permeability may contribute to the biological behavior of tumors. Evidence for increased generation of kinins and kinin receptors detection in different types of cancer has been reported (Leeb-Lundberg et al. 2005).

Summary

Considering the knowledge gathered since the classical pharmacological models were established and the more recently gene target animal models, much has been changed concerning the kinin receptors function. In the beginning, the kinin receptors were first implicated with pain and inflammation. Nowadays they are still important in this area of study; however, they have been implicated with different diseases like asthma, arthritis, sepsis, kidney disease, hypertension, cardiopathy, diabetes, and cancer among others. In the last years, new implications of kinin receptors in obesity and immunology are described, as well as interaction of kinin receptors and other proteins like ACE and AT1 receptor. These implications will bring new possibilities for therapies involving kinin ligands (agonists and antagonists). Moreover, ongoing tests with new drugs affecting the KKS are on the way. The main goal is to develop more potent and tissue specific ligands, with increased disposability, central permeability, and reduced collateral effects. The field of study of these receptors is wide and promising.

References

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Biophysics DepartmentUniversidade Federal de São PauloSão PauloBrazil