Glial cell line-derived neurotrophic factor–mediated enteric neuronal survival involves glycogen synthase kinase-3β phosphorylation and coupling with 14-3-3

Glial cell line-derived neurotrophic factor (GDNF) promotes the growth and survival of enteric neurons, but the mechanisms involved are poorly understood. GDNF is known to promote the survival of enteric neurons through activation of the PI3-Kinase/Akt signaling pathway. We investigated the role of glycogen synthase kinase-3β (GSK-3β) in enteric neuronal survival, and the ability of GDNF to regulate the activity of GSK-3β using primary rat embryonic enteric neurons. GDNF, through activation of the PI3-kinase pathway enhanced the phosphorylation of GSK-3β at its N-terminal serine-9 residue, and promoted the association of GSK-3β with 14-3-3. Transfection of a constitutively active S9A-GSK-3β mutant prevented the survival effects of GDNF, whereas a dominant negative GSK-3β construct prevented GDNF withdrawal-induced cell death. Increased GSK-3β activity was associated with an increase in tau phosphorylation. Thus, GDNF promotes enteric neuronal survival by modulating GSK-3β and its downstream target tau. Inhibitors of GSK-3β activity may have therapeutic potential in improving enteric neuronal survival.