Regulation of α(2B)-Adrenergic Receptor Cell Surface Transport by GGA1 and GGA2.
Regulation of α(2B)-Adrenergic Receptor Cell Surface Transport by GGA1 and GGA2.
复制标题
DOI：
10.1038/srep37921
复制
发表时间：
2016-11-30
影响因子：
4.6
通讯作者：
Wu G
中科院分区：
文献类型：
--
作者：
Zhang M;Huang W;Gao J;Terry AV;Wu G
控制新合成的G蛋白偶联受体（GPCRs）靶向功能目的地的分子机制仍不清楚。在此，我们确定了高尔基体定位的、γ-adaptin ear domain同源性、ADP核糖基化因子结合蛋白1和2（GGA 1和GGA 2）在α 2B-肾上腺素能受体（α2B-AR）（一种原型GPCR）的细胞表面转运中的作用，并研究了其潜在机制。我们证明，通过shRNA和siRNA敲低GGA 1和GGA 2显著降低了细胞表面诱导表达的α2B-AR的表达，并将受体阻滞在核周区域。敲低各GGA均显著抑制原代皮层神经元α2B-AR的树突表达。一致地，耗尽GGA 1和GGA 2减弱受体介导的信号转导，测量为ERK 1/2活化和cAMP抑制。虽然全长α2B-AR与GGA 2而不是GGA 1相关，但发现其第三个细胞内环直接与GGA 1和GGA 2相互作用。更有趣的是，相互作用结构域的进一步作图显示GGA 1铰链区和GGA 2 GAE结构域结合到环的多个亚结构域。这些研究已经确定了GGA家族蛋白在细胞表面GPCR的前向运输中的重要功能并揭示了其新机制。
The molecular mechanisms that control the targeting of newly synthesized G protein-coupled receptors (GPCRs) to the functional destinations remain poorly elucidated. Here, we have determined the role of Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins 1 and 2 (GGA1 and GGA2) in the cell surface transport of α2B-adrenergic receptor (α2B-AR), a prototypic GPCR, and studied the underlying mechanisms. We demonstrated that knockdown of GGA1 and GGA2 by shRNA and siRNA significantly reduced the cell surface expression of inducibly expressed α2B-AR and arrested the receptor in the perinuclear region. Knockdown of each GGA markedly inhibited the dendritic expression of α2B-AR in primary cortical neurons. Consistently, depleting GGA1 and GGA2 attenuated receptor-mediated signal transduction measured as ERK1/2 activation and cAMP inhibition. Although full length α2B-AR associated with GGA2 but not GGA1, its third intracellular loop was found to directly interact with both GGA1 and GGA2. More interestingly, further mapping of interaction domains showed that the GGA1 hinge region and the GGA2 GAE domain bound to multiple subdomains of the loop. These studies have identified an important function and revealed novel mechanisms of the GGA family proteins in the forward trafficking of a cell surface GPCR.
登录
查看更多内容
DOI：
10.1111/j.1600-0854.2012.01351.x
发表时间：
2012-06
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Dong C;Nichols CD;Guo J;Huang W;Lambert NA;Wu G
通讯作者：
Wu G
影响因子：
64.5
作者：
COLLEY, NJ;BAKER, EK;ZUKER, CS
通讯作者：
ZUKER, CS
影响因子：
4.8
作者：
Doray, B;Bruns, K;Kornfeld, S
通讯作者：
Kornfeld, S
DOI：
10.1124/jpet.109.161489
发表时间：
2010-04-01
影响因子：
3.5
作者：
Dong, Chunmin;Zhang, Xiaoping;Wu, Guangyu
通讯作者：
Wu, Guangyu
DOI：
10.1083/jcb.200408165
发表时间：
2004-11-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ang AL;Taguchi T;Francis S;Fölsch H;Murrells LJ;Pypaert M;Warren G;Mellman I
通讯作者：
Mellman I