Fig. 14
The possible intracellular route of TDZ in human astrocytes. Schematic overview of the possible TDZ/ERK/AKT/JNK signalling pathways in our experimental model is depicted. In astrocytes, the 5-HT1AR is coupled to Gαi/o proteins [83]; its activation by TDZ decreases ERK phosphorylation via Gαi/o protein ([a]) [84, 85], and increases AKT phosphorylation ([b]) [92, 93]. The PI3K/AKT pathway may contribute to deregulate JNK. Moreover, AKT phosphorylates GSK3, blocking in turn its activity, leading to alteration of astrocyte metabolism ([c]) [92, 93]. TDZ enhances CREB and BDNF transcription via a PI3K/AKT pathway ([d]). 5-HT2A/CRs may couple to Gαq proteins [40]; TDZ, showing an antagonistic activity on 5HT2A/CRs, may reduce ERK activation ([e]). TDZ antagonizes α-ARs ([f]), contributing to reduce JNK phosphorylation. Abbreviations: AC: adenylyl cyclase; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; PKC: protein kinase C; CREB: cAMP response element-binding protein; BDNF: brain-derived nerve factor; ERK: extracellular signal-regulated kinase; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; GSK3: glycogen synthase kinase 3; PDK1: 3-phosphoinositide dependent protein kinase-1; JNKs: c-Jun N-terminal kinases; PLC: Phospholipase C; PIP2: phosphatidylinositol 4,5-bisphosphate; IP3: inositol trisphosphate; DAG: diacyl-glycerol