Bradykinin receptor B2 explained

Bradykinin receptor B₂ is a G-protein coupled receptor for bradykinin, encoded by the BDKRB2 gene in humans.

Mechanism

The B₂ receptor (B₂R) is a G protein-coupled receptor, probably coupled to G_q and G_i. A 2022 Nature cryo-EM study of human B₂R-G_q complexes by Jinkeng Sheng et al. investigated the proximal activation mechanisms of B₂R. Sheng et al. propose that upon B₂R binding bradykinin or kallidin to a "bulky orthosteric binding pocket," the phenylalanine F8 or F9 residue of bradykinin or kallidin respectively interacts with a "conserved toggle switch" W283. This hydrophobic interaction facilitates the outward movement of transmembrane domain 6 (TM6) of B₂R on the cytoplasmic side of the membrane, as well as outward movement of F279, a key residue within the conserved PIF motif of GPCRs (involving proline, isoleucine and phenylalanine). This rearrangement of the PIF motif disrupts the ionic lock formed by the DRY motif and pushes the NPxxY motif towards the activated state, opening an "intracellular cleft" for insertion of the α5-helix of G_q. ^[1]

G_q stimulates phospholipase C to increase intracellular free calcium and G_i inhibits adenylate cyclase. Furthermore, the receptor stimulates the mitogen-activated protein kinase pathways. It is ubiquitously and constitutively expressed in healthy tissues.

The B₂ receptor forms a complex with angiotensin converting enzyme (ACE), and this is thought to play a role in cross-talk between the renin-angiotensin system (RAS) and the kinin–kallikrein system (KKS). The heptapeptide angiotensin (1-7) also potentiates bradykinin action on B₂ receptors.^[2]

Kallidin also signals through the B₂ receptor. An antagonist for the receptor is Hoe 140 (icatibant).^[3]

Function

The 9 amino acid bradykinin peptide elicits several responses including vasodilation, edema, smooth muscle spasm and nociceptor stimulation.

Gene

Alternate start codons result in two isoforms of the protein.^[4]

See also

• Bradykinin receptor

Further reading

• Duchêne J, Schanstra J, Cellier E, Bascands JL, Girolami JP . [30 years: Happy birthday, GPCR. The bradykinin B2 receptor: an alternative and antiproliferative pathway] . Nephrologie . 23 . 1 . 39–41 . 2002 . 11908480 .
• Ariza AC, Bobadilla NA, Halhali A . [Endothelin 1 and angiotensin II in preeeclampsia] . Revista de Investigacion Clinica . 59 . 1 . 48–56 . 2007 . 17569300 .
• Hess JF, Borkowski JA, Young GS, Strader CD, Ransom RW . Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor . Biochemical and Biophysical Research Communications . 184 . 1 . 260–268 . April 1992 . 1314587 . 10.1016/0006-291X(92)91187-U .
• Eggerickx D, Raspe E, Bertrand D, Vassart G, Parmentier M . Molecular cloning, functional expression and pharmacological characterization of a human bradykinin B2 receptor gene . Biochemical and Biophysical Research Communications . 187 . 3 . 1306–1313 . September 1992 . 1329734 . 10.1016/0006-291X(92)90445-Q .
• Kammerer S, Braun A, Arnold N, Roscher AA . The human bradykinin B2 receptor gene: full length cDNA, genomic organization and identification of the regulatory region . Biochemical and Biophysical Research Communications . 211 . 1 . 226–233 . June 1995 . 7779089 . 10.1006/bbrc.1995.1800 .
• Braun A, Kammerer S, Böhme E, Müller B, Roscher AA . Identification of polymorphic sites of the human bradykinin B2 receptor gene . Biochemical and Biophysical Research Communications . 211 . 1 . 234–240 . June 1995 . 7779090 . 10.1006/bbrc.1995.1801 .
• Ma JX, Wang DZ, Ward DC, Chen L, Dessai T, Chao J, Chao L . Structure and chromosomal localization of the gene (BDKRB2) encoding human bradykinin B2 receptor . Genomics . 23 . 2 . 362–369 . September 1994 . 7835885 . 10.1006/geno.1994.1512 . free .
• Powell SJ, Slynn G, Thomas C, Hopkins B, Briggs I, Graham A . Human bradykinin B2 receptor: nucleotide sequence analysis and assignment to chromosome 14 . Genomics . 15 . 2 . 435–438 . February 1993 . 7916737 . 10.1006/geno.1993.1084 .
• Menke JG, Borkowski JA, Bierilo KK, MacNeil T, Derrick AW, Schneck KA, Ransom RW, Strader CD, Linemeyer DL, Hess JF . 6 . Expression cloning of a human B1 bradykinin receptor . The Journal of Biological Chemistry . 269 . 34 . 21583–21586 . August 1994 . 8063797 . 10.1016/S0021-9258(17)31844-6 . free .
• Hess JF, Borkowski JA, Macneil T, Stonesifer GY, Fraher J, Strader CD, Ransom RW . Differential pharmacology of cloned human and mouse B2 bradykinin receptors . Molecular Pharmacology . 45 . 1 . 1–8 . January 1994 . 8302267 .
• McIntyre P, Phillips E, Skidmore E, Brown M, Webb M . Cloned murine bradykinin receptor exhibits a mixed B1 and B2 pharmacological selectivity . Molecular Pharmacology . 44 . 2 . 346–355 . August 1993 . 8394991 .
• AbdAlla S, Godovac-Zimmermann J, Braun A, Roscher AA, Müller-Esterl W, Quitterer U . Structure of the bradykinin B2 receptors' amino terminus . Biochemistry . 35 . 23 . 7514–7519 . June 1996 . 8652530 . 10.1021/bi9601060 .
• Isami S, Kishikawa H, Araki E, Uehara M, Kaneko K, Shirotani T, Todaka M, Ura S, Motoyoshi S, Matsumoto K, Miyamura N, Shichiri M . 6 . Bradykinin enhances GLUT4 translocation through the increase of insulin receptor tyrosine kinase in primary adipocytes: evidence that bradykinin stimulates the insulin signalling pathway . Diabetologia . 39 . 4 . 412–420 . April 1996 . 8777990 . 10.1007/BF00400672 . 2243985 .
• Dalemar LR, Ivy Jong YJ, Wilhelm B, Baenziger NL . Protein kinases A and C rapidly modulate expression of human lung fibroblast B2 bradykinin receptor affinity forms . European Journal of Cell Biology . 69 . 3 . 236–244 . March 1996 . 8900488 .
• Soskic V, Nyakatura E, Roos M, Müller-Esterl W, Godovac-Zimmermann J . Correlations in palmitoylation and multiple phosphorylation of rat bradykinin B2 receptor in Chinese hamster ovary cells . The Journal of Biological Chemistry . 274 . 13 . 8539–8545 . March 1999 . 10085087 . 10.1074/jbc.274.13.8539 . free .
• Cassano G, Susca F, Lippe C, Guanti G . Two B1 and B2 bradykinin receptor antagonists fail to inhibit the Ca2+ response elicited by bradykinin in human skin fibroblasts . General Pharmacology . 32 . 2 . 239–244 . February 1999 . 10188626 . 10.1016/S0306-3623(98)00275-4 .
• Efremov R, Truong MJ, Darcissac EC, Zeng J, Grau O, Vergoten G, Debard C, Capron A, Bahr GM . 6 . Human chemokine receptors CCR5, CCR3 and CCR2B share common polarity motif in the first extracellular loop with other human G-protein coupled receptors implications for HIV-1 coreceptor function . European Journal of Biochemistry . 263 . 3 . 746–756 . August 1999 . 10469138 . 10.1046/j.1432-1327.1999.00553.x .
• Marrero MB, Venema VJ, Ju H, He H, Liang H, Caldwell RB, Venema RC . Endothelial nitric oxide synthase interactions with G-protein-coupled receptors . The Biochemical Journal . 343 Pt 2 . Pt 2 . 335–340 . October 1999 . 10510297 . 1220558 . 10.1042/0264-6021:3430335 .
• Reyes-Cruz G, Vázquez-Prado J, Müller-Esterl W, Vaca L . Regulation of the human bradykinin B2 receptor expressed in sf21 insect cells: a possible role for tyrosine kinases . Journal of Cellular Biochemistry . 76 . 4 . 658–673 . January 2000 . 10653985 . 10.1002/(SICI)1097-4644(20000315)76:4<658::AID-JCB14>3.0.CO;2-7 . 30042149 .
• Golser R, Gorren AC, Leber A, Andrew P, Habisch HJ, Werner ER, Schmidt K, Venema RC, Mayer B . 6 . Interaction of endothelial and neuronal nitric-oxide synthases with the bradykinin B2 receptor. Binding of an inhibitory peptide to the oxygenase domain blocks uncoupled NADPH oxidation . The Journal of Biological Chemistry . 275 . 8 . 5291–5296 . February 2000 . 10681501 . 10.1074/jbc.275.8.5291 . free .

External links

• Web site: Bradykinin Receptors: B₂ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Notes and References

1. Shen J, Zhang D, Fu Y, Chen A, Yang X, Zhang H . Cryo-EM structures of human bradykinin receptor-G_q proteins complexes . Nature Communications . 13 . 1 . 714 . February 2022 . 35132089 . 8821558 . 10.1038/s41467-022-28399-1 . 2022NatCo..13..714S .
2. Fernandes L, Fortes ZB, Nigro D, Tostes RC, Santos RA, Catelli De Carvalho MH . Potentiation of bradykinin by angiotensin-(1-7) on arterioles of spontaneously hypertensive rats studied in vivo . Hypertension . 37 . 2 Pt 2 . 703–709 . February 2001 . 11230360 . 10.1161/01.hyp.37.2.703 . 17827058 .
3. Wirth K, Hock FJ, Albus U, Linz W, Alpermann HG, Anagnostopoulos H, Henk S, Breipohl G, König W, Knolle J . 6 . Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies . British Journal of Pharmacology . 102 . 3 . 774–777 . March 1991 . 1364852 . 1917928 . 10.1111/j.1476-5381.1991.tb12249.x .
4. Web site: Entrez Gene: BDKRB2 bradykinin receptor B2.