Rimler Avi, Jockers Ralf, Lupowitz Zipora, Zisapel Nava
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
J Mol Neurosci. 2007;31(1):1-12. doi: 10.1007/BF02686113.
Nuclear localization of androgen receptors (ARs) is essential for their activity. Melatonin induces AR nuclear exclusion via increase in cGMP, calcium, and protein kinase C (PKC) activation, presumably through G-protein(s). The effects of regulators of G-protein signaling (RGS) on AR localization were studied in AR-expressing PC3 cells. Gi-specific RGS10 inhibited melatonin but not cGMP-induced AR nuclear exclusion, independent of androgen. No evidence for Gq activation by melatonin was found. However, Gi/Gq-selective RGS4 inhibited AR nuclear exclusion downstream of PKC activation--an effect that was abrogated by constitutively active Gq. RGS10 and RGS4, but not RGS2, ablated the inhibitory effects of melatonin on AR reporter gene activity. For the first time, these data show regulation by Gi and Gi-specific RGS protein-mediated AR nuclear exclusion, which is potentially important in the treatment of AR-dependent cancers and neurodegenerative disorders. They also reveal a role for a Gq protein downstream of PKC activation in AR nuclear localization.
雄激素受体（ARs）的核定位对其活性至关重要。褪黑素通过增加环鸟苷酸（cGMP）、钙和蛋白激酶C（PKC）的激活诱导AR核排除，推测是通过G蛋白介导的。在表达AR的PC3细胞中研究了G蛋白信号调节剂（RGS）对AR定位的影响。Gi特异性的RGS10抑制褪黑素诱导的而非cGMP诱导的AR核排除，且与雄激素无关。未发现褪黑素激活Gq的证据。然而，Gi/Gq选择性的RGS4在PKC激活下游抑制AR核排除——这一效应被组成型活性Gq消除。RGS10和RGS4而非RGS2消除了褪黑素对AR报告基因活性的抑制作用。这些数据首次表明由Gi和Gi特异性RGS蛋白介导的AR核排除调控，这在AR依赖性癌症和神经退行性疾病的治疗中可能具有重要意义。它们还揭示了PKC激活下游的Gq蛋白在AR核定位中的作用。
