The alpha 2A adrenergic receptor evokes activation of p70S6 kinase through G protein and transactivation of EGFR

Abstract

The function of α2A adrenergic receptor (α2AAR) has been implicated in a wide range of physiological activities. The molecular mechanisms behind these activities are topics under intensive investigation. At the cellular level, stimulation of the α2AAR leads to propagation of a number of signaling cascades, such as MAPK, Akt and p70S6 kinase (p70S6K) pathways. In the current study, we characterized α2AAR‐mediated p70S6K activation. Stimulation of the α2AAR evokes activation of p70S6K in both embryonic fibroblasts (MEF) and neurons in a dose‐dependent manner. To delineate the molecular pathway of the α2AAR‐mediated p70S6K activation, pharmacological inhibitors for potential signaling molecules involved were applied on cells. Pertussis toxin treatment of cells blocked α2AAR‐mediated p70S6K activation, indicating the involvement of G proteins in this process. When cells were treated with an EGFR inhibitor or a PI3K inhibitor, α2AAR‐mediated p70S6K activation was also blocked. Additionally, rapamycin treatment diminished α2AAR‐mediated p70S6K activation. Taken together, these data suggests that α2AAR‐mediated activation of p70S6K is a G protein‐dependent process and achieved through transactivation of EGFR, which subsequently activates PI3K and mTOR to stimulate p70S6K. This research was supported by a NIH grant MH081917 (QW) and an AHA SDG grant 0630103N (QW).