Figure 7.

Proposed Mechanism of Action for α-TOH in TH+ DRGN

With adequate α-TOH (left), constitutive activity of the RAR-related orphan receptor alpha (RORA) transcription factor is maintained, increasing IP₃R1 transcription (Gold et al., 2003, Sarachana and Hu, 2013). Although there is evidence that vitE can affect the plasma membrane structure and bind to signaling enzymes to affect their activity (Zingg, 2015, Habermehl et al., 2005), we propose in this model that signaling through the PLC/IP₃/IP₃R1 axis maintains Ca²⁺ homeostasis. VitE can suppress PLC activity (Domijan et al., 2014) and, by stimulating DAGK (Koya et al., 1997), DAG is removed and PKC inhibited, providing a protective effect. With α-TOH deficiency (right), cholesterol is oxidized and resulting oxysterols repress constitutive RORA activity (Wang et al., 2010), leading to decreased IP₃R1 transcription. ROS activate the PLC/IP₃/IP₃R1 axis (Servitja et al., 2000, Vaarmann et al., 2010); however, without sufficient IP₃R1, [Ca²⁺]_i cannot increase. Additionally, loss of DAGK stimulation increases DAG and PKC. We propose this leads to the identified alterations in membrane excitability and activation of apoptotic pathways in DRGNs. BK= big potassium channel; DAG = diaglycerol; DAGK= diaglycerol kinase; IP₃ = inositol triphosphate; IP₃R1 = inositol 1,4,5 triphosphate receptor 1; PIP₂ = phosphatidylinositol 4,5-bisphosphate; PKC = protein kinase C; PLC = phospholipase C; RORA= RAR-related orphan receptor alpha; ROS = reactive oxygen species.