Cloning, sequence analysis and expression of the gene encoding the mouse bradykinin B2 receptor

doi:10.1016/0378-1119(94)90162-7

Gene

Volume 149, Issue 2, 18 November 1994, Pages 283-288

https://doi.org/10.1016/0378-1119(94)90162-7 Get rights and content

Abstract

The bradykinin B₂ receptor (B₂R) mediates most of the biological effects of kinins. In the present study, we have cloned and sequenced the gene (B₂R) from a mouse embryonic stem (ES) cell genomic library. Mouse B₂R is 7 kb in length containing three exons of 0.3, 0.23 and 3.7 kb separated by two introns of 2.5 and 0.41 kb. The first and second exons are noncoding while the third exon contains the full-length coding region and a long 3′ noncoding region. An ATG translation start codon, TGA stop codon and a polyadenylation signal (AATAAA) were identified in the third exon. B₂R encodes a protein of 41470 Da and 366 amino acids (aa) forming seven transmembrane (TM) domains. At the aa level, B₂R shares 91 and 82% sequence identity with the rat and human B₂R, respectively. In the 5′ flanking region, a consensus TATA box, a putative cAMP-response element, a putative phorbol ester-response element, a putative AP-1-binding site and a putative IL-6-response element were identified. Southern blot analysis following reverse transcription and PCR showed that B_t2R is expressed in most mouse tissues, except the liver and spleen, which is consistent with the wide distribution of B₂R activity as deduced from pharmacological studies.

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Cited by (46)

Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease
2015, Neuropeptides
Citation Excerpt :
In the rat hippocampus, a single dose of BK promotes hyperphosphorylation of the Tau protein eliciting memory and learning impairment (Wang and Wang, 2002). Kinin B2R is widely distributed in the CNS, being described in several nuclei of rats (Cholewinski et al., 1991; Couture and Lindsey, 2000; Viel et al., 2008), mice (Ma et al., 1994a), guinea pigs (Lopes et al., 1983; Sharif and Whiting, 1991; Murone et al., 1997; Fujiwara et al., 1988), bovine cattle (Kozlowski et al., 1998) and humans (Ma et al., 1994b; Raidoo et al., 1996) as assessed by RT-PCR, immunohistochemistry and autoradiography. Alzheimer's disease (AD) is a progressive neurodegenerative disease with severe impact on learning and memory.
Alzheimer's disease (AD) is characterized by cognitive decline, presence of amyloid-beta peptide (Aβ) aggregates and neurofibrillary tangles. Kinins act through B1 and B2 G-protein coupled receptors (B1R and B2R). Chronic infusion of Aβ peptide leads to memory impairment and increases in densities of both kinin receptors in memory processing areas. Similar memory impairment was observed in C57BL/6 mice (WTAβ) but occurred earlier in mice lacking B2R (KOB2Aβ) and was absent in mice lacking B1R (KOB1Aβ). Thus, the aim of this study was to evaluate the participation of B1R and B2R in Aβ peptide induced cognitive deficits through the evaluation of densities of kinin receptors, synapses, cell bodies and number of Aβ deposits in brain of WTAβ, KOB1Aβ and KOB2Aβ mice. An increase in B2R density was observed in both WTAβ and KOB1Aβ in memory processing related areas. KOB1Aβ showed a decrease in neuronal density and an increase in synaptic density and, in addition, an increase in Aβ deposits in KOB2Aβ was observed. In conclusion, memory preservation in KOB1Aβ, could be due to the increase in densities of B2R, suggesting a neuroprotective role for B2R, reinforced by the increased number of Aβ plaques in KOB2Aβ. Our data point to B2R as a potential therapeutic target in AD.
Control of ENaC-mediated sodium reabsorption in the distal nephron by Bradykinin
2015, Vitamins and Hormones
Citation Excerpt :
The physiological actions of the KKS are mainly mediated by BK and have both beneficial (vasodilation, natriuresis, diuresis, decrease in insulin resistance, etc.) and detrimental (pain, inflammation, allergy, and edema) consequences (Regoli et al., 2012). B2R are constitutively expressed in many tissues, such as smooth muscles, neurons, vascular endothelium, and kidney epithelial cells (Ma, Wang, Chao, & Chao, 1994). In contrast, expression of B1R is low during normal physiology but is markedly upregulated by tissue injury and inflammation (Marceau, Larrivee, Saint-Jacques, & Bachvarov, 1997).
Kinins, such as Bradykinin (BK), are peptide hormones of the kallikrein–kinin system. Apart from being a vasodilator, BK also increases urinary sodium excretion to reduce systemic blood pressure. It is becoming appreciated that BK modulates function of the epithelial Na⁺ channel in the distal part of the renal nephron to affect tubular sodium reabsorption. In this chapter, we outline the molecular details, as well as discuss the physiological relevance of this regulation for the whole organism sodium homeostasis and setting chronic blood pressure.
The Influence of Gender on Cough Reflex Sensitivity
2004, Principles of Gender-Specific Medicine
Kinin receptors in cultured rat microglia
2004, Neurochemistry International
Kinins are produced and act at the site of injury and inflammation in various tissues. They are likely to initiate a particular cascade of inflammatory events, which evokes physiological and pathophysiological responses including an increase in blood flow and plasma leakage. In the central nervous system (CNS), kinins are potent stimulators of the production and release of pro-inflammatory mediators represented by prostanoids and cytotoxins. They are known to induce neural tissue damage. Many of the cytotoxins such as cytokines and free radicals and prostanoids are released from glial cells. Among glial cells, astrocytes and oligodendrocytes are known to possess bradykinin (BK) B₂ receptors that phosphoinositide (PI) turnover and raise intracellular Ca²⁺ concentration. The presence of bradykinin receptors in microglia has been of great significance. We recently showed that rat primary microglia express kinin receptors. In resting microglia, B₂ receptors but not B₁ receptors are expressed. When the microglia are activated by bradykinin, B₁ receptors are up-regulated, while B₂ receptors are down-regulated. As observed in other glial cells, electrophysiological measurements suggest that B₂ receptors in phosphoinositide turnover and intracellular Ca²⁺ concentration in microglia. Release of cytotoxins is likely consequent upon the activation of BK receptors. Our study provides the first evidence that microglia express functional kinin receptors and suggests that microglia play an important role in CNS inflammatory responses.
Structure of the mammalian kinin receptor gene locus
2002, International Immunopharmacology
The genes encoding the two kinin receptors, B1 and B2, are closely linked on the same chromosome in human, mouse, and rat. In this article, we present the organisation of the B1B2 locus in these mammals. This organisation was obtained by comparing the kinin receptor mRNA sequences of man and mouse with the sequence of chromosomes 14 and 12, respectively. We found that the two genes are located in tandem orientation, separated by only 7.8 kb in mice and 12 kb in humans. The distance of the two genes on rat chromosome 6 was determined by long-range PCR to be 9.5 kb. The organisation of the two genes encoding the kinin receptors is similar in the three species, except that the human B1 gene harbors an additional exon, which may originate from the insertion of an Alu repetitive sequence during evolution. Moreover, the human and rat, but not the murine, B2 genes carry an alternatively spliced exon between exons 2 and 3, termed exon 2b.
Upregulation of bradykinin B2 receptor expression by neurotrophic factors and nerve injury in mouse sensory neurons
2002, Molecular and Cellular Neuroscience
Bradykinin B2 receptor mRNA was detected at low levels, both by RT-PCR and by in situ hybridization, in freshly isolated dorsal root ganglia (DRG) and in ganglia cultured in the absence of neurotrophic factors, but was strongly upregulated by culture in the presence of nerve growth factor (NGF). The effect of NGF is mediated via TrkA receptors. The related neurotrophins, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4, were ineffective in upregulating B2 mRNA, but a small upregulation was seen with the unrelated neurotrophin glial cell line-derived neurotrophic factor (GDNF). Surface membrane B2 receptor expression, detected by immunofluorescence using a B2-specific antibody, was low in outgrowing axons cultured in the absence of neurotrophic factors, but was elevated by addition of NGF or GDNF. Conditioned media prepared by incubating injured nerve, skin, or muscle had a similar effect to NGF in upregulating B2 mRNA and protein expression, and the activity was largely removed by neutralization of NGF in the conditioned medium with an anti-NGF antibody. After nerve crush injury in vivo an enhancement in B2 mRNA expression was seen, peaking after 7 days and returning to precrush levels after 14 days. In all conditions tested, the proportion of neurons expressing B2 mRNA remained the same at around 23% of small neurons, suggesting that upregulation only occurs in the B2-positive neurons. These experiments show that NGF, and to a lesser extent GDNF, upregulates the expression of bradykinin B2 mRNA and B2 receptor protein in the surface membrane of DRG neurons and that NGF is an important factor responsible for upregulating bradykinin B2 receptor expression after nerve crush injury in vivo.

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Cloning, sequence analysis and expression of the gene encoding the mouse bradykinin B2 receptor

Abstract

Cell

Life Sci.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Bradykinin antagonists

Annu. Rev. Pharmacol. Toxicol.

Bioregulation of kinins: kallikreins, kininogens and kininases

Pharmacol. Rev.

Cloning, sequence analysis and expression of the gene encoding the mouse bradykinin B₂ receptor