GABAB receptor association with the PDZ scaffold Mupp1 alters receptor stability and function
GABAB receptor association with the PDZ scaffold Mupp1 alters receptor stability and function
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DOI：
10.1074/jbc.m607695200
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发表时间：
2007-02-09
影响因子：
4.8
通讯作者：
Hall, Randy A.
中科院分区：
文献类型：
--
作者：
Balasubramanian, Srividya;Fam, Sami R.;Hall, Randy A.
γ-氨基丁酸，B型（GABA（B））受体是介导中枢神经系统中缓慢抑制性突触传递的异二聚体G蛋白偶联受体。为了鉴定可能调节GABAB受体（GABA（B）R）功能的新型相互作用伴侣，我们针对最近创建的96个不同PDZ（PSD-95/Dlg/ZO-1同源性）结构域的蛋白质组阵列筛选GABA（B）R2羧基末端。筛选鉴定了三个表现出与GABABR 2相互作用的特异性PDZ结构域：Mupp 1 PDZ 13、PAPIN PDZ 1和Erbin PDZ。生化分析证实，全长Mupp 1和PAPIN与细胞中的GABABR 2相互作用。通过对受体羧基末端的点突变破坏GABABR 2与PDZ支架的相互作用，显著降低了受体稳定性并减弱了GABAB受体信号传导的持续时间。通过内源性Mupp 1的小干扰RNA敲低来模拟突变GABABR 2羧基末端对受体稳定性和信号传导的影响。这些发现表明，GABA，受体稳定性和信号可以通过GABABR 2与PDZ支架蛋白Mupp 1的相互作用来调节，这可能有助于中枢神经系统中GABA，受体的细胞特异性调节。
gamma-Aminobutyric acid, type B (GABA(B)) receptors are heterodimeric G protein-coupled receptors that mediate slow inhibitory synaptic transmission in the central nervous system. To identify novel interacting partners that might regulate GABAB receptor (GABA(B)R) functionality, we screened the GABA(B)R2 carboxyl terminus against a recently created proteomic array of 96 distinct PDZ (PSD-95/Dlg/ZO-1 homology) domains. The screen identified three specific PDZ domains that exhibit interactions with GABABR2: Mupp1 PDZ13, PAPIN PDZ1, and Erbin PDZ. Biochemical analysis confirmed that full-length Mupp1 and PAPIN interact with GABABR2 in cells. Disruption of the GABABR2 interaction with PDZ scaffolds by a point mutation to the carboxyl terminus of the receptor dramatically decreased receptor stability and attenuated the duration of GABAB receptor signaling. The effects of mutating the GABABR2 carboxyl terminus on receptor stability and signaling were mimicked by small interference RNA knockdown of endogenous Mupp1. These findings reveal that GABA, receptor stability and signaling can be modulated via GABABR2 interactions with the PDZ scaffold protein Mupp1, which may contribute to cell-specific regulation of GABA, receptors in the central nervous system.