Arrestin Interactions During LH Receptor Desensitization

促黄体生成激素（LH）受体是与G蛋白（最典型的是Gs）偶联的七跨膜受体，其激活腺苷酸环化酶以传递第二信使信号。LH受体的信号转导受到称为脱敏的分子机制的调节。尽管LH受体的脱敏可能涉及受体功能、G蛋白功能或下游效应物的衰减，但由于与抑制蛋白分子的关联，受体无法激活其各自的G蛋白似乎是导致受体脱敏的关键事件。我们实验室最近的研究已经阐明了β-arrestin与LH受体相互作用所必需的各种蛋白质，以及β-arrestins在信号转导中的潜在新作用。我推测，在一个完整的细胞内，ARF核苷酸结合位点开放器（ARNO）激活ADP核糖基化因子6（ARF 6），导致β-arrestin-1从其膜对接位点释放。一旦释放，β-arrestin-1与激活的LH受体结合，并通过异源三聚体G蛋白抑制进一步的信号传导。然后，抑制蛋白-受体复合物募集Src和/或Grb-2以启动不同的信号传导途径，Akt信号传导途径。为了验证这一假设，我提出了三个具体的目标，以澄清参与释放和信号转导的β-抑制蛋白激活LH受体后的分子机制。

The luteinizing hormone (LH) receptor is a seven transmembrane spanning receptor coupled to G proteins, most typically Gs, which activates adenylyl cyclase to transduce a second messenger signal. Signal transduction by the LH receptor is tempered by a molecular mechanism known as desensitization. Although desensitization of the LH receptor may involve attenuation of receptor function, G protein function, or the downstream effector, the inability of receptors to activate their respective G-protein due to associations with arrestin molecules appears to be a key event leading to receptor desensitization. Recent studies from our laboratory have elucidated various proteins necessary for beta-arrestin interaction with the LH receptor and a potential new role for beta-arrestins in signal transduction. I hypothesize that within an intact cell ARF nucleotide-binding site opener (ARNO) activates ADP ribosylation factor 6 (ARF6) which leads to the release of beta-arrestin-1 from its membrane docking site. Once released, beta-arrestin-1 binds to the activated LH receptor and inhibits further signaling through heterotrimeric G proteins. The arrestin-receptor complex then recruits Src and/or Grb-2 to initiate a different signaling pathway, the Akt signaling pathway. To test this hypothesis, I propose three specific aims to clarify the molecular mechanisms involved in the release of and signal transduction via beta- arrestin following activation of the LH receptor.