Identification of a soluble form phospholipase A2 receptor as a circulating endogenous inhibitor for secretory phospholipase A2.
Venomous snakes have various types of phospholipase A(2) inhibitory proteins (PLIs) in their circulatory system to protect them from attack by their own phospholipase A(2)s (PLA(2)s). Here we show the first evidence for the existence of circulating PLI against secretory PLA(2)s (sPLA(2)s) in mammals. In mouse serum, we detected specific binding activities of group IB and X sPLA(2)s, which was in contrast with the absence of binding activities in serum prepared from mice deficient in PLA(2) receptor (PLA(2)R), a type I transmembrane glycoprotein related to the C-type animal lectin family. Western blot analysis after partial purification with group IB sPLA(2) affinity column confirmed the identity of serum sPLA(2)-binding protein as a soluble form of PLA(2)R (sPLA(2)R) that retained all of the extracellular domains of the membrane-bound receptor. Both purified sPLA(2)R and the recombinant soluble receptor having all of the extracellular portions blocked the biological functions of group X sPLA(2), including its potent enzymatic activity and its binding to the membrane-bound receptor. Protease inhibitor tests with PLA(2)R-overexpressing Chinese hamster ovary cells suggested that sPLA(2)R is produced by cleavage of the membrane-bound receptor by metalloproteinases. Thus, sPLA(2)R is the first example of circulating PLI that acts as an endogenous inhibitor for enzymatic activities and receptor-mediated functions of sPLA(2)s in mice.
Higashino Ki
Ken-ichi
K
Shionogi Research Laboratories, Shionogi & Co., Ltd. 12-4 Sagisu, 5-Chome, Fukushima-ku, Osaka 553-0002, Japan.
Yokota
Yasunori
Y
Ono
Takashi
T
Kamitani
Shigeki
S
Arita
Hitoshi
H
Hanasaki
Kohji
K
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002845:Chromatography; D006224:Cricetinae; D020128:Inhibitory Concentration 50; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000097:blood* / Q000737:chemistry*; D054507:Receptors, Phospholipase A2; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors
D008024:Ligands; C516357:Pla2r1 protein, mouse; D011956:Receptors, Cell Surface; D054507:Receptors, Phospholipase A2; D011994:Recombinant Proteins; D010741:Phospholipases A; D054467:Phospholipases A2