Pharmacological and functional characterization of bradykinin B2 receptor in human prostate.
The objective of this study was to pharmacologically characterize bradykinin receptors, a component of the kallikrein-kinin system, in normal human prostate cells. In primary cultured human prostate stromal cells, bradykinin, but not [des-Arg9]bradykinin or [des-Arg10]kallidin, produced calcium mobilization or inositol phosphates accumulation with potencies (pEC50) of 8.8+/-0.2 and 8.2+/-0.2, respectively. This was consistent with abundance of bradykinin B2 mRNA over bradykinin B1 mRNA in prostate stromal cells. Although the prostate epithelial cells (prostate epithelium, BPH-1, and PC-3) expressed mRNA for bradykinin B2 receptors (albeit in lesser amounts than stromal cells), bradykinin was not functionally efficacious in the epithelial cells. Increasing concentrations of D-arginyl-L-arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4-tetrahhydro-3-isoquinolinecarbonyl-L-(2alpha,3beta,7alphabeta)-octahydro-1H-indole-2-carbonyl-L-arginine (HOE-140), a bradykinin B2-selective peptide antagonist, attenuated bradykinin concentration-response curves in human prostate stromal cells with apparent estimate of affinity similar to that for the human bradykinin B2 receptor. Bradykinin (10 nM) caused proliferation of prostate stromal cells and phosphorylated extracellular signal-regulated kinases (ERK-1 and ERK-2) that were blocked by HOE-140 (1 microM). This study demonstrated that, in primary cultures of normal human prostate stromal cells, bradykinin activates bradykinin B2 receptors that may play a significant role in proliferation via activation of ERK-1/2 pathways.
Srinivasan
Dinesh
D
Roche Pharmaceuticals, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Kosaka
Alan H
AH
Daniels
Donald V
DV
Ford
Anthony P D W
AP
Bhattacharya
Anindya
A
D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003124:Colorimetry; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043783:Receptor, Bradykinin B1 / Q000187:drug effects / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007295:Inositol Phosphates; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium