Apolipoprotein E and mimetic peptide initiate a calcium-dependent signaling response in macrophages

Apolipoprotein E (ApoE) is a 34-kDa cholesterol transport protein that also possesses immunomodulatory properties. In this study, ive demonstrate that ApoE initiates a signaling cascade in murine peritoneal macrophages that l eads to increased production of inositol triphosphate with mobilization of intracellular Ca2+ stores. This cascade is inhibited by pretreatment with r eceptor-associated protein and Ni2+, and it is mediated by a pertussis toxi n-sensitive G protein. These properties are characteristic of signal transd uction induced via ligand binding to the cellular receptor, lipoprotein rec eptor-related protein. A peptide derived from the receptor-binding region o f ApoE also initiates signal transduction in a manner similar to that of th e intact protein, suggesting that this isolated region is sufficient for si gnal transduction. The ApoE-mimetic peptide competed for binding with the i ntact protein, confirming that they both interact with the same site. ApoE- dependent signal transduction might play a role in mediating the functional properties of this lipoprotein.