Type-2 bradykinin receptor

Han E, MacFarlane R, Mulhgan A, Scafidi J, Davis AR Increased vascular permeabihty in Cl inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002 8 1057-1063. 

Figure 5 shows a stereoview of the selected ligand-receptor complex chosen on the basis of best agreement with the results of these mutagenesis studies. None of the other four putative complexes were in agreement with this experimental data and were not considered further. Of particular significance in this work was that the trans-membrane residue Glu49, when mutated to alanine, showed no adverse effect on bradykinin receptor affinity with respect to rat wild type. A similar result was reported for the... 

M. Sato, R. M. Engelman, H. Otani, N. Maulik, J. Rousou, J. Flack, D. W. Deaton, D. K. Das, Myocardial protection by preconditioning of heart with losartan, an angiotensin II type 1-receptor blocker. Implication of bradykinin-dependent and bradykinin-independent mechanisma, Circulation 120, suplIII III—346—III—351 (2000). 

Figure 108.1. Diagrammatic representation of the nociceptor (adapted from Julius and Basbaum, 2001 [8]).The elements shown In the figure that are known to modulate the nociceptors in an excitatory manner are tyrosine kinase A (TrkA), the receptor for nerve growth (actor, the transient receptor potential channel (TRP) V, bradykinin receptor(s), the tetrodotoxin-resistant, sensory neuron-specific Na+ channel (NaJ. 8), the acid-sensing ion channels (ASIC), the adenosine receptor, and prostaglandin (PG)Ej receptors. Inhibitory modulation of the nociceptor is achievable via stimulation of the cannabinoid type 1 receptors (CB,).

Bradykinin has long been recognized as one of the G protein-coupled receptors that can modulate both pain and inflammation (see Figures 108.1 and 108.2). Two receptor types have been described B1 and B2. The B2 receptor is expressed constitutively in a wide variety of tissues including nociceptive neurons whereas the B1 receptor lies dormant. In inflammatory states the B1 receptor is induced/acti-vated and can generate both pain and inflammation. Stimulation of the bradykinin receptor leads to activation of a phosphoinositide signaling pathway, the release of intracellular calcium ions, and activation of a kinase system. This ultimately opens TRPVl channels in the sensory nerve membranes, so enhancing nociception. 

While the potential role of bradykinin antagonists is significant, years of research have not been able to adequately define the type of bradykinin receptor that is responsible for pain and inflammation in humans. A B2 antagonist (HOE140 Icatibant) was evaluated clinically but failed to alleviate acute pain. To date there is no B1 antagonist and a clear clinical candidate for B2 is not on the horizon. Nevertheless, the proven involvement of bradykinin in inflammatory pain renders an antagonist of the relevant B-receptor a worthwhile target... 

Bradykinin is a kinin that mediates the physiological processes accompanying acute and chronic pain and inflammation. Two classes of bradykinin receptors, Biand B2, are known to be activated upon kinin release. " The B2 receptor is present in many cell types and tissues under normal physiological conditions and is believed to be responsible for the immediate acute pain response after... 

Gelperin, D., Mann, D., Del Valle, J. and Wiley, J. Bradykinin (BK) increases cytosolic calcium in cultured rat myenteric neurons via BK-2 type receptors coupled to mobilization of extracellular and intracellular sources of calcium Evidence that calcium influx is prostaglandin dependent. /. Pharmacol. Exp. Ther. 271 507-514,1994. 

Apart from their anti-inflammatory activity the NSAIDs also show, dependent on the condition and the type of pain, considerable analgesic efficacy. In some forms of postoperative pain the NSAID s can be as efficacious as opioids, especially when prostaglandins, bradykinin and histamine, which are released by inflammation, have caused sensitization of pain receptors to normally painless stimuli. In Table 4 some advantages and disadvantages of NSAID s and opioids are compared. Although analgesic effects at peripheral or central neurons cannot be excluded completely, most studies indicate that... 

The biologic actions of kinins are mediated by specific receptors located on the membranes of the target tissues. Two types of kinin receptors, termed Bj and B2, have been defined based on the rank orders of agonist potencies. (Note that here stands for bradykinin, not for -adrenoceptor.) Bradykinin displays the highest affinity in most B2 receptor systems, followed by lys-bradykinin and then by met-lys-bradykinin. One exception is the B2 receptor that mediates contraction of venous smooth muscle this appears to be most sensitive to lys-bradykinin. Recent evidence suggests the existence of two B2-receptor subtypes, which have been termed B2A and B2B. 

Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated three-fold beyond normal in patients with Alzheimer s disease, implicating bradykinin as a participant in the peripheral inflammatory processes associated with that disease [13]. 

Following our hypothesis that bradykinin adopts a C-terminal (3 turn upon complexation with the receptor, the , / backbone dihedral angles in the tetrapeptide corresponding to the C-terminus of bradykinin (Ser-Pro-Phe-Agr) were constrained in a harmonic fashion (force constant = 15 Kcal A-1 mof ) to values that define a type If [3-turn [43]. This tetrapeptide probe was then systematically translated about the interior of a theoretical box inscribing the rat... 

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