**9. Conclusions**

Both receptors belong to the superfamily of receptors that have seven transmembrane domains coupled to G proteins, differing both in primary structure, expression, and regulation of their

Two types of G protein‐coupled receptors have been found that bind to BK mediating its response in pathophysiological conditions. To summarize, there are stimulatory G proteins (Gs and Gq) and inhibitory G proteins (Gi). Gs binds to GTP and activates adenylate cyclase, increasing the amount of intracellular cAMP. Gi binds to GTP and inactivates adenylate cyclase, indirectly reducing the amount of intracellular cAMP. Gq binds to GTP and activates PLC, increasing the amount of DAG, IP, and intracellular Ca++. Transduction pathways stimu‐ lated by kinins have been extensively investigated in endothelial cells, where BKR1 interacts

in phospholipase C (PLC) causes it to act on their specific substrate, phosphatidylinositol biphosphate (PIP2), hydrolyzing it generating the two metabolites: inositol triphosphate (IP<sup>3</sup>

and diacylglycerol (DAG). IP3 binds to a specific receptor (IP3R) in the endoplasmic reticu‐ lum facilitating the release of intracellular Ca++. IP3, possibly together with its metabolite, IP4, can regulate calcium channels of the plasma membrane allowing the entry of extracellular calcium into the cell [87, 88]. The other metabolite of PIP2 hydrolysis, DAG, is responsible for the activation of protein kinase C (PKC) [89, 90]. PKC consists of one polypeptide chain with two functional domains: (a) a hydrophobic domain for binding to the cell membrane and (b) a hydrophilic domain, which possesses catalytic function. PKC at cellular rest is found in an inactive form in the cytosol, but once stimulated by DAG together with Ca++ ions it translocates to the cell membrane to exert its function of protein kinase in serine and threonine

and C. The kinin‐induced increase

)

with Gq and Gi proteins, using the same signaling pathways as BKR2 (**Figure 10**).

BKR2 binds to G proteins and activates phospholipases A<sup>2</sup>

**Figure 10.** Bradykinin receptors and G‐protein–coupled receptor‐signaling pathway.

tissue distribution [85, 86].

168 A Comprehensive Review of Urticaria and Angioedema

C1‐INH‐HAE is a rare inherited disorder, characterized by recurrent AE attacks in various regions of the body. C1‐INH‐AAE is an acquired disease usually due to the presence of anti‐C1‐INH autoantibodies. The lack of C1‐INH leads to inappropriate activation of the kallikrein‐kinin system and release of BK, a vasoactive mediator.

nC1‐INH‐HAE is another inherited form of AE, with no C1‐INH deficiency, but a probable increase in BK formation due to mutation in exon 9 of *F12* gene with subsequent hyper‐ activability.

BK (common final mediator of BK‐AE) is a linear nonapeptide (with sequence Arg1‐Pro2‐ Pro3‐Gly4‐Phe5‐Ser6‐Pro7‐Phe8‐Arg9) produced endogenously in humans and other mam‐ mals as a result of the proteolytic activity of kallikrein on kininogens.

Some drugs that inhibit the catabolism of BK have been implicated in the development of AE. These include ACEIs, DPP‐IV inhibitors, APP inhibitors, and NEP inhibitors.
