Molecular Cloning and Functional Characterization of a Mouse Bradykinin B1 Receptor Gene

Pesquero, João Bosco; Pesquero, Jorge L.; Oliveira, Sérgio Ferreira de; Roscher, Adelbert A.; Metzger, Rainer; Ganten, Detlev; Bäder, Michael

doi:10.1006/bbrc.1996.0384

Cited by 95 publications

(38 citation statements)

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“…The mouse kinin B1-receptor gene was cloned (12), and B1-deficient mice were generated by gene-targeting technology ( Fig. 1 A and B).…”

Section: Resultsmentioning

confidence: 99%

“…The B1-receptor gene was cloned from a genomic library of 129͞SvJ mice in FIXII (12). The targeting vector was generated by flanking the neomycinresistance gene with a 1.0-kb genomic fragment 5Ј of the B1-coding region and a 7.0-kb fragment 3Ј of the B1-coding region.…”

Section: Methodsmentioning

confidence: 99%

“…However, despite the detection of mRNA for the B1 receptor in dorsal root ganglia, its role in pain transmission has remained elusive (11). To clarify the functions of the B1 receptor, we have cloned the murine B1-receptor gene (12) and generated mice lacking this protein by using gene targeting technology. In B1-deficient mice, the hypotensive response to LPS injection, a model for sepsis, was significantly blunted.…”

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confidence: 99%

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Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

Pesquero

Araújo

Heppenstall

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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343

259

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Kinins are important mediators in cardiovascular homeostasis, inflammation, and nociception. Two kinin receptors have been described, B1 and B2. The B2 receptor is constitutively expressed, and its targeted disruption leads to salt-sensitive hypertension and altered nociception. The B1 receptor is a heptahelical receptor distinct from the B2 receptor in that it is highly inducible by inflammatory mediators such as bacterial lipopolysaccharide and interleukins. To clarify its physiological function, we have generated mice with a targeted deletion of the gene for the B1 receptor. B1 receptor-deficient animals are healthy, fertile, and normotensive. In these mice, bacterial lipopolysaccharide-induced hypotension is blunted, and there is a reduced accumulation of polymorphonuclear leukocytes in inflamed tissue. Moreover, under normal noninflamed conditions, they are analgesic in behavioral tests of chemical and thermal nociception. Using whole-cell patch-clamp recordings, we show that the B1 receptor was not necessary for regulating the noxious heat sensitivity of isolated nociceptors. However, by using an in vitro preparation, we could show that functional B1 receptors are present in the spinal cord, and their activation can facilitate a nociceptive reflex. Furthermore, in B1 receptor-deficient mice, we observed a reduction in the activitydependent facilitation (wind-up) of a nociceptive spinal reflex. Thus, the kinin B1 receptor plays an essential physiological role in the initiation of inflammatory responses and the modulation of spinal cord plasticity that underlies the central component of pain. The B1 receptor therefore represents a useful pharmacological target especially for the treatment of inflammatory disorders and pain.D iseases of the cardiovascular system as well as inflammatory diseases that often lead to pain are of increasing importance for health care in aging populations. Kinins have been known for some time to be important mediators of cardiovascular homeostasis, inflammation, and nociception (1). They are probably the first mediators released in injured tissue from kininogens either by plasma kallikrein, which is activated early in the coagulation cascade, or tissue kallikrein, which is activated by proteases released at injured sites. Surprisingly, the therapeutic value of intervention in the kallikrein-kinin system has not been fully explored. The two known receptors for kinins, B1 and B2, might be suitable pharmacological targets to treat chronic inflammatory and cardiovascular diseases. The B2 receptor binds the major effector peptide of the kallikrein-kinin system, which is bradykinin (BK) in rodents and kallidin in humans. Deletion of the B2 receptor in mice leads to salt-sensitive hypertension and altered nociception (2-4). Like the B2 receptor, the B1 receptor is a heptahelical receptor, but unlike B2 receptors, it is not widely expressed in normal tissue but is highly inducible by inflammatory mediators like bacterial lipopolysaccharide (LPS) and cytokines and does not desensitize after...

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“…The mouse kinin B1-receptor gene was cloned (12), and B1-deficient mice were generated by gene-targeting technology ( Fig. 1 A and B).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

Pesquero

Araújo

Heppenstall

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

343

259

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“…Whereas the B 2 receptor is responsive to the intact kinins, bradykinin (BK) 1 and Lys-BK (kallidin), the B 1 receptor has a higher affinity for the carboxypeptidase metabolites of kinins, des-Arg 9 -BK and des-Arg 10 -kallidin (4). Expression cloning of B 1 and B 2 receptor cDNAs confirms the existence of these two subtypes and reveals that they both belong to the G proteincoupled superfamily of receptors with seven transmembrane domains (5)(6)(7)(8)(9)(10)(11). Activation of the kinin receptors leads to generation of inositol phosphate and transient increases in intracellular Ca 2ϩ levels via coupling to phospholipase C, involving, at least, the G i , G q/11 , and G 13 proteins (12)(13)(14)(15).…”

mentioning

confidence: 99%

Transcription Factor Nuclear Factor κB Regulates the Inducible Expression of the Human B1 Receptor Gene in Inflammation

Chao

1998

Journal of Biological Chemistry

128

101

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“…), который расположен во второй внеклеточной петле его молекулы [45]. Дальнейшие исследования выявили довольно высокую степень гомологии (68-78%) между Б 1 Р человека и Б 1 Р некоторых других видов млекопитающих (кролика, мыши, крысы) [46][47][48].…”

Section: структурные особенности рецепторов кининов (б 1 р и б 2 р)unclassified

Ace inhibitors - activators of kinin receptors

Kugaevskaya

Elisseeva

2011

BIOMED KHIM

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Angiotensin converting enzyme (ACE) inhibitors are widely used for treatment of cardiovascular diseases. The effects of ACE inhibitors on the human bradykinin receptors were investigated. The mode of action of ACE inhibitors is considered. There is evidence that ACE inhibitors exert effects on the vascular system that cannot be attributed simply to the inhibition of ACE activity and accumulation of locally produced bradykinin. ACE inhibitors augment bradykinin effects on receptors indirectly by inducing cross-talk between ACE and the B2 receptor when enzyme and receptor molecules are sterically close, possibly forming a heterodimer. ACE inhibitors activate B1 receptors directly and independently of ACE via the zink-binding consensus sequence HEXXH, which is present in B1, but not in B2 receptor. Particular structure of B2 and B1 are represented, as well as receptor amino acids coupled with the G-proteins. Activation of kinin receptors by ACE inhibitors leads to clinically beneficial effects of ACE inhibitors.

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Molecular Cloning and Functional Characterization of a Mouse Bradykinin B1 Receptor Gene

Cited by 95 publications

References 0 publications

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

Transcription Factor Nuclear Factor κB Regulates the Inducible Expression of the Human B1 Receptor Gene in Inflammation

Ace inhibitors - activators of kinin receptors

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