Low‐density lipoprotein receptor‐related protein mediates in PC12 cell cultures the inhibition of nerve growth factor‐promoted neurite outgrowth by pregnancy zone protein and α2‐macroglobulin

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Abstract
Human pregnancy zone protein (PZP) is a major pregnancy‐associated plasma protein closely related to human α2‐macroglobulin (α2M). It has been demonstrated that monoamine‐activated forms of human and rat α2M and rat α1M can bind to TrkA and, respectively, inhibit and stimulate NGF‐promoted neurite outgrowth, Trk phosphorylation, and intracellular signal transduction in PC12 cells. However, the effect of PZP on neurons is unknown, and the molecular mechanism of neuroinhibition by monoamine‐activated α2M is still unclear. In this report, we show that methylamine‐activated PZP (MA‐PZP), like MA‐α2M, inhibits in a dose‐dependent way the NGF‐promoted neurite extension and TrkA phosphorylation in PC12 cells. On the other hand, normal PZP (N‐PZP) had little or no effect. In addition, the inhibitory effect of activated α‐macroglobulins (αMs) was reversible upon its removal from the cell culture. In addition, PZP, as well as α2M, is neuroinhibitory without being directly cytotoxic. It is known that the activated αMs bind to the multiligand receptor termed low‐density lipoprotein receptor‐related protein (LRP) and that the receptor‐associated protein (RAP) specifically blocks uptake of all known LRP ligands. To investigate the potential role of LRP in neuromodulation by activated PZP/α2M, the effect of RAP on the neuroinhibitory activities of these αMs was also studied. Data presented here show that RAP blocked the neurite‐ and Trk‐inhibitory activities of both MA‐PZP and MA‐α2M, whereas RAP itself had no neuromodulatory effect. Hence, we conclude that these data suggest that the LRP receptor and its αM ligands may play a role in regulating Trk receptors.

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