Binding of rat α 1 ‐inhibitor‐3‐methylamine to the α 2 ‐macroglobulin signaling receptor induces second messengers

Binding of receptor‐recognized forms of tetrameric human α 2 ‐macroglobulin (α 2 M*) to a macrophage signaling receptor induces cAMP synthesis, increases in inositol 1,4,5‐triphosphate (IP 3 ) synthesis, and a concomitant rise in cytosolic free calcium ([Ca 2+ ] i ). The α 2 M* signaling receptor is coupled to a pertussis‐toxin insensitive G protein. Binding of α 2 M* also occurs to the low density lipoprotein receptor‐related protein/α 2 M receptor (LRP/α 2 MR), but this binding does not induce signal transduction. Rat α 1 ‐inhibitor‐3 (α 1 I 3 ) is a monomeric member of the α‐macroglobulin/complement superfamily. Like α 2 M, it can react with proteinases or methylamine which induces a conformational change causing activated α 1 I 3 to bind to LRP/α 2 MR. We now report that α 1 I 3 ‐methylamine binds to the macrophage α 2 M* signaling receptor inducing a rapid rise in the synthesis of IP 3 with a subsequent 1.5‐ to 3‐fold rise in [Ca 2+ ] i . α 1 I 3 ‐methylamine binding to macrophages also caused a statistically significant elevation in cAMP. Native α 1 I 3 , like α 2 M, was unable to induce signal transduction. α 1 I 3 forms a complex with α 1 ‐microglobulin, which has a distinct conformation from α 1 I 3 and is recognized by LRP/α 2 MR. This complex also induces an increase in [Ca 2+ ] i comparable to the effect of α 1 I 3 ‐methylamine on macrophages. It is concluded that activation of α 1 I 3 by methylamine or binding of α 1 ‐microglobulin causes similar conformational changes in the inhibitor, exposing the receptor recognition site for the α 2 M* signaling receptor, as well as for LRP/α 2 MR. © 1996 Wiley‐Liss, Inc.