SIGNALING PATHWAYS COUPLED TO ACTIVATION OF THE KININ B1 RECEPTOR ; ADVANCES IN PROTEIN KINASES

Kinins are a group of bioactive peptides, which are formed by an endogenous enzymatic cascade consisting of precursor substrates called kininogens and the proteolytic kallikrein enzymes (kininogenases). So far, two kinin-releasing enzymes (kininogenases) have been characterized, plasma (hKB1/LKLB1) and tissue (hK1/KLK1) kallikreins (Fig. 1). Both enzymes are serine proteases that are found in glandular cells, neutrophils, and biological fluids. Kininogens are multifunctional proteins involved in cascade reactions during inflammation (Bhoola et al., 1992), and more recently in carcinogenesis (Bhoola et al., 1992; 2001; Leeb-Lundberg et al., 2005). Kinins namely bradykinin (BK) and kallidin (Lys-BK) are among the most potent pro-inflammatory vasoactive peptides generated during tissue injury and noxious stimulation. BK and Lys-BK undergo metabolic degradation at a variable rate by amino-, carboxy- and endopeptidases found in tissues and biological fluids. The most physiologically relevant enzymes are carboxypeptidase N (from plasma) and carboxypeptidase M (from cell membranes), which remove the carboxy-terminal Arg present at end of the kinin molecule, resulting in the formation of the active metabolites desArg9-BK (DBK) and des-Arg10-kallidin, known also as Lys-des-Arg9-BK (LDBK) (Fig. 1). Furthermore, neutral endopeptidase 24.11 (CD10, enkephalinase) and angiotensin I converting enzyme, act as dipeptidyl carboxypeptidases by removing the dipeptide Phe8- Arg9 from the carboxy terminus end of BK or Lys-BK (Couture et al., 2004). It is important to mention that endopeptidase 24.15 and angiotensin I converting enzyme cleave the dipeptide Ser6-Pro7 from bradykinin 1-7 (BK1-7) to produce bradykinin 1-5 (BK1-5), one of the final metabolites of BK and DBK that possesses the longer half-life of this peptide family. The half-life of kinins depends on the rate and site of destruction, most rapid in the circulation, but less so in the extracellular fluid space and by cells. Actually, in plasma the half-life of BK and LDBK ...