A novel cross-talk between endothelin and ErbB receptors controlling glutamate transporter expression in astrocytes

Abstract

The endothelin and epidermal growth factor (EGF) systems are central to the control of reactive brain processes and are thought to partly exert these tasks by endothelin-induced transactivation of the epidermal growth factor receptor (EGFR) Here we show that beyond EGFR transactivation, endothelins prevent the ligand-induced internalization of the EGFR. We unravel that endothelins abrogate internalization of the EGFR by either promoting the formation of "internalization-deficient" EGFR/ErB2-heterodimers or by activating c-Abl kinase, a negative regulator of EGFR internalization. We further provide evidence that this cross-talk is operational in the control of astrocytic glutamate transport. Specifically, we establish that the inhibitory effects exerted by endothelins on basal as well as EGF-induced expression of the major astroglial glutamate transporter subtype, glutamate transporter 1, are a direct consequence of the endothelin-dependent retention of the EGFR at the cell surface. Together our findings unravel a previously unknown cross-talk between endothelin and epidermal growth factor receptors, which may have implications for a variety of pathological conditions. We recently demonstrated that endothelin-1 (ET-1) potently overrides the stimulatory influences of EGF on the expression of the major glial glutamate transporter subtype, GLT-1. Here, we provide evidence that ET-1 abrogates EGF-induced increases in GLT-1 expression by preventing internalization of ligand-bound EGFR. This previously unknown interplay between endothelins and the EGFR could well have broad functions in the diseased brain. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.