Abstract: | Binding of receptor-recognized forms of tetrameric human α2-macroglobulin (α2M*) to a macrophage signaling receptor induces cAMP synthesis, increases in inositol 1,4,5-triphosphate (IP3) synthesis, and a concomitant rise in cytosolic free calcium (Ca2+]i). The α2M* signaling receptor is coupled to a pertussis-toxin insensitive G protein. Binding of α2M* also occurs to the low density lipoprotein receptor-related protein/α2M receptor (LRP/α2MR), but this binding does not induce signal transduction. Rat α1-inhibitor-3 (α1I3) is a monomeric member of the α-macroglobulin/complement superfamily. Like α2M, it can react with proteinases or methylamine which induces a conformational change causing activated α1I3 to bind to LRP/α2MR. We now report that α1I3-methylamine binds to the macrophage α2M* signaling receptor inducing a rapid rise in the synthesis of IP3 with a subsequent 1.5- to 3-fold rise in Ca2+]i. α1I3-methylamine binding to macrophages also caused a statistically significant elevation in cAMP. Native α1I3, like α2M, was unable to induce signal transduction. α1I3 forms a complex with α1-microglobulin, which has a distinct conformation from α1I3 and is recognized by LRP/α2MR. This complex also induces an increase in Ca2+]i comparable to the effect of α1I3-methylamine on macrophages. It is concluded that activation of α1I3 by methylamine or binding of α1-microglobulin causes similar conformational changes in the inhibitor, exposing the receptor recognition site for the α2M* signaling receptor, as well as for LRP/α2MR. © 1996 Wiley-Liss, Inc. |