Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Sci Signal. 2013 May 7;6(274):ra31. doi: 10.1126/scisignal.2003705.
Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr(52), which then promoted the dephosphorylation of CAR at Thr(38) by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR.
苯巴比妥是一种中枢神经系统抑制剂，它还间接激活核受体组成激活的芳烃受体 (CAR)，促进肝脏中的药物和能量代谢以及细胞生长（和死亡）。我们发现苯巴比妥通过抑制表皮生长因子受体 (EGFR) 信号来激活 CAR。苯巴比妥与 EGFR 结合并强烈抑制 EGF 的结合，从而阻止 EGFR 的激活。这种 EGFR 信号的中断诱导激活的 C 激酶 1 (RACK1) 在 Tyr(52)处去磷酸化，然后通过蛋白磷酸酶 2A 的催化核心亚基促进 CAR 在 Thr(38)处去磷酸化。研究结果表明，苯巴比妥诱导的 CAR 去磷酸化和激活机制是通过其与 EGFR 的直接相互作用和抑制来介导的。
