Subtype-specific neuronal differentiation of PC12 cells transfected with α₂-adrenergic receptors

Cells of the PC12 rat pheochromocytoma cell line acquire characteristics of sympathetic neurons under appropriate treatment. Stably transfected PC12 cells expressing individual α2-adrenergic receptor (α2-AR) subtypes were used to assess the role of α2-ARs in neuronal differentiation and to characterise the signalling pathways activated by the α2-AR agonist epinephrine in these cells. The effects of α2-AR activation were compared with the differentiating action and the signalling mechanisms of nerve growth factor (NGF). Epinephrine induced neuronal differentiation of PC12α2 cells through α2-AR activation in a subtype-dependent manner, internalization of all human α2-AR subtypes, and activation of mitogen-activated protein kinase (MAPK) and the serine-threonine protein kinase Akt. Epinephrine and NGF showed synergism in their differentiating effects. The MAPK kinase (MEK-1) inhibitor PD 98059 abolished the differentiating effect of epinephrine indicating that the differentiation is dependent on MAPK activation. Activating protein-1 (AP-1) DNA-binding activity was increased after epinephrine treatment in all three PC12α2 subtype clones. Evaluation of the potential physiological consequences of these findings requires further studies on endogenously expressed α2-ARs in neuronal cells.