Role of metalloproteinase‐dependent EGF receptor activation in α1‐adrenoceptor‐stimulated MAP kinase phosphorylation in GT1‐7 neurons

Publisher Website
Google Scholar
Abstract
Adrenoceptors (ARs) are involved in the regulation of gonadotropin‐releasing hormone (GnRH) release from native and immortalized hypothalamic (GT1‐7) neurons. However, the AR‐mediated signaling mechanisms and their functional significance in these cells are not known. Stimulation of GT1‐7 cells with the α1‐AR agonist, phenylephrine (Phe), causes phosphorylation of extracellular signal‐regulated kinases 1 and 2 (ERK1/2) mitogen‐activated protein (MAP) kinases that is mediated by protein kinase C (PKC)‐dependent transactivation of the epidermal growth factor receptor (EGF‐R). Phe stimulation causes shedding of the soluble ligand, heparin‐binding EGF (HB‐EGF), as a consequence of matrix metalloproteinase (MMP) activation. Phe‐induced phosphorylation of the EGF‐R, and subsequently of Shc and ERK1/2, was attenuated by inhibition of MMP or HB‐EGF with the selective inhibitor, CRM197, or by a neutralizing antibody. In contrast, phosphorylation of the EGF‐R, Shc and ERK1/2 by EGF and HB‐EGF was independent of PKC and MMP activity. Moreover, inhibition of Src attenuated ERK1/2 responses by Phe, but not by HB‐EGF and EGF, indicating that Src acts upstream of the EGF‐R. Consistent with a potential role of reactive oxygen species (ROS), Phe‐induced phosphorylation of EGF‐R was attenuated by the antioxidant, N‐acetylcysteine. These data suggest that activation of the α1‐AR causes phosphorylation of ERK1/2 through activation of PKC, ROS and Src, and shedding of HB‐EGF, which binds to and activates the EGF‐R.

This publication has 62 references indexed in Scilit: