Ja William W, Wiser Ofer, Austin Ryan J, Jan Lily Y, Roberts Richard W
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
ACS Chem Biol. 2006 Oct 24;1(9):570-4. doi: 10.1021/cb600345k.
Intracellular Galpha subunits represent potential therapeutic targets for a number of diseases. Here we describe three classes of new molecules that modulate G protein signaling by direct targeting of Galpha. Using messenger RNA display, we have identified unique peptide sequences that bind Galpha i1 . Functionally, individual peptides were found that either enhance or repress basal levels of G protein-activated inwardly rectifying potassium (GIRK) channel signaling, a downstream effector of G protein activation, indicating that the peptides directly turn G proteins on or off in vivo . A third functional class acts as a signaling attenuator; basal GIRK channel activity is unaffected but responses to repeated G protein activation are reduced. These data demonstrate that G protein-directed ligands can achieve physiological effects similar to those resulting from classical receptor targeting and may serve as leads for developing new classes of therapeutics.
细胞内的Gα亚基是多种疾病潜在的治疗靶点。在此，我们描述了三类通过直接靶向Gα来调节G蛋白信号传导的新分子。利用信使核糖核酸展示技术，我们鉴定出了与Gα i1结合的独特肽序列。在功能上，发现单个肽要么增强要么抑制G蛋白激活的内向整流钾通道（GIRK）信号传导的基础水平，GIRK通道信号传导是G蛋白激活的下游效应器，这表明这些肽在体内直接开启或关闭G蛋白。第三类功能分子作为信号衰减器；GIRK通道的基础活性不受影响，但对重复的G蛋白激活的反应减弱。这些数据表明，靶向G蛋白的配体可以产生与经典受体靶向所产生的生理效应相似的效果，并可能成为开发新型治疗药物的先导。
