Molecular biology of the kallikrein-kinin system: from structure to function

Abstract

The participation of the kallikrein-kinin system, comprising the serine proteases kallikreins, the protein substrates kininogens and the effective peptides kinins, in some pathological processes like hypertension and cardiovascular diseases is still a matter of controversy. The use of different experimental set-ups in concert with the development of potent and specific inhibitors and antagonists for the system has highlighted its importance but the results still lack conclusivity. Over the last few years, transgenic and gene-targeting technologies associated with molecular biology tools have provided specific information about the elusive role of the kallikrein-kinin system in the control of blood pressure and electrolyte homeostasis. cDNA and genomic sequences for kinin receptors B2 and B1 from different species were isolated and shown to encode G-protein-coupled receptors and the structure and pharmacology of the receptors were characterized. Transgenic animals expressing an overactive kallikrein-kinin system were established to study the cardiovascular effects of these alterations and the results of these investigations further corroborate the importance of this system in the maintenance of normal blood pressure. Knockout animals for B2 and B1 receptors are available and their analysis also points to the role of these receptors in cardiovascular regulation and inflammatory processes. In this paper the most recent and relevant genetic animal models developed for the study of the kallikrein-kinin system are reviewed, and the advances they brought to the understanding of the biological role of this system are discussed. Correspondence

Protein kinase C (PKC)-δ/-ε mediate the PKC/Akt-dependent phosphorylation of extracellular signal-regulated kinases 1 and 2 in MCF-7 cells stimulated by bradykinin

“…Bradykinin (BK) belongs to the kallikrein-kinin system and two G-protein-coupled receptors (GPCRs) have been recognised, namely, B 1 and B 2 receptors (Regoli & Barabè 1980, Vavrek & Stewart 1985, Ma et al 1994, el-Dahr et al 1997, Pesquero & Bader 1998. In various cell types the B 2 receptor, as other GPCRs, mediates most of the biological actions of BK via the activation of G q/11 protein, the increase of free intracellular calcium concentration ([Ca 2+ ] i ) and the activation of various protein kinase C (PKC) isoforms (Enomoto et al 1995, AnkorinaStark et al 1997, Wiernas et al 1998.…”

Bradykinin stimulates cell proliferation through an extracellular-regulated kinase 1 and 2-dependent mechanism in breast cancer cells in primary culture

“…BK exerts its action via two known receptors, namely, B 1 and B 2 receptors (Regoli & Barabé 1980, Vavrek & Stewart 1985, Ma et al 1994, el-Dahr et al 1997, Pesquero & Bader 1998. The kallikrein-kinin system is implicated in tumourigenesis through the actions of kinins (Robert & Gulick 1989, Maeda et al 1999, since released kinins increase vascular blood flow and promote the supply of nutrients and oxygen to the tumour.…”

Role of Bradykinin B2 and B1 Receptors in the Local, Remote, and Systemic Inflammatory Responses That Follow Intestinal Ischemia and Reperfusion Injury

“…The effects of these peptides may be direct or associated with the stimulation of secondary mediators of inflammation, including prostanoids, tachykinins, cytokines, mast cell-derived products, and NO (7,8). Kinins, of which bradykinin appears to be the most important member, act on two distinct receptors: B 2 and B 1 receptors (7,9,10). B 2 R is constitutively expressed on various cell types, including endothelial cells, nerve fibers, leukocytes, and mast cell (8,11).…”