Complement C5a receptor antagonism by protamine and poly-L-Arg on human leukocytes.
It is shown that protamine selectively and dose-dependently inhibits complement C5a-induced leukocyte responses such as histamine release from basophils, chemiluminescence and beta-glucuronidase release from neutrophils. Protamine produces parallel rightward displacements of the C5a dose-response curves. The inhibitory capacity of the polypeptide is reversible and disappears following repeated washing of exposed cells. In neutrophils poly-L-Arg similarly and specifically antagonizes C5a-induced chemiluminescence and enzyme release. This polymer alone, however, degranulates basophils and neutrophils, leading to histamine and enzyme release, respectively. It is concluded that on human neutrophils the arginine-rich polycations protamine and poly-L-Arg exhibit a competitive C5a receptor antagonism. In addition, protamine inhibits the C5a receptors on basophils. It is hypothesized that molecular conformations of the arginine-rich polycations might bind reversibly to, and block negatively charged groups at the C5a-receptor sites.
Olsen
U B
UB
Department of Pharmacology, NOVO Industri A/S, Bagsvaerd, Denmark.
Selmer
J
J
Kahl
J U
JU
D001491:Basophils / Q000187:drug effects; D003182:Complement C5; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects*; D008163:Luminescent Measurements; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D011479:Protamines / Q000494:pharmacology*; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000187:drug effects*
D003182:Complement C5; D010455:Peptides; D011479:Protamines; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C015462:polyarginine; D006632:Histamine; D005966:Glucuronidase