J. Neurochem. (2010) 115, 1007–1023.
Abstract
Stimulation of β‐adrenoceptors activates the canonical adenylate cyclase pathway (via Gs protein) but can also evoke phosphorylation of extracellular‐regulated kinases 1 and 2 (ERK1/2) via Gs/Gi switching or β‐arrestin‐mediated recruitment of Src. In primary cultures of mouse astrocytes, activation of the former of these pathways required micromolar concentrations of the β1/β2‐adrenergic agonist isoproterenol, that acted on β1‐adrenoceptors, whereas the latter was activated already by nanomolar concentrations, acting on β2 receptors. Protein kinase A activity was required for Gs/Gi switching, which was followed by Ca2+ release from intracellular stores and Giα‐ and metalloproteinase‐dependent transactivation of the epidermal growth factor receptor (EGFR; at its Y1173 phophorylation site), via its receptor‐tyrosine kinase, β‐arrestin 1/2 recruitment, and MAPK/ERK kinase‐dependent ERK1/2 phosphorylation. ERK1/2 phosphorylation by Src activation depended on β‐arrestin 2, but not β‐arrestin 1, was accompanied by Src/EGFR co‐precipitation and phosphorylation of the EGFR at the Src‐phosphorylated Y845 site and the Y1045 autophosphorylation site; it was independent of transactivation but dependent on MAPK/ERK kinase activity, suggesting EGFR phosphorylation independently of the receptor‐tyrosine kinase or activation of Ras or Raf directly from Src. Most astrocytic consequences of activating either pathway (or both) are unknown, but morphological differentiation and increase in glial fibrillary acidic protein in response to dibutyryl cAMP‐mediated increase in cAMP depend on Gs/Gi switching and transactivation.