Lipid rafts are triage centers for multimeric and monomeric thyrotropin receptor regulation
Lipid rafts are triage centers for multimeric and monomeric thyrotropin receptor regulation
复制标题
DOI：
10.1210/en.2006-1580
复制
发表时间：
2007-07-01
期刊：
影响因子：
4.8
通讯作者：
Davies, T. F.
中科院分区：
文献类型：
--
作者：
Latif, R.;Ando, T.;Davies, T. F.
TSH受体（TSHR）是甲状腺细胞表面的一种七螺旋G蛋白偶联受体，是甲状腺的主要自身抗原和生理调节因子。与其他G蛋白偶联受体不同，TSHR经历其胞外域的翻译后切割，导致质膜上存在几种形式的受体。我们先前假设，为了实现TSH配体或TSHR自身抗体信号传导的高保真度和特异性，TSHR可以区室化成质膜内的微区。为了支持这一假设，我们先前已经证明TSHR位于表达TSHR的细胞质膜上富含GM（1）神经节苷脂的脂筏中。在这项研究中，我们进一步探讨了不同形式的TSHR驻留在脂筏。我们研究了促甲状腺激素释放激素受体转染细胞和大鼠甲状腺细胞，使用非洗涤剂生化分析和受体脂筏共定位。利用生物化学的方法，我们观察到，单体受体存在于筏和非筏部分的细胞表面在稳态。我们还证明了受体的多聚体形式优先分配到脂质微域中。不同的TSHR形式，包括多聚体，动态调节受体特异性和postreceptor-specific调制器。促甲状腺激素配体和促甲状腺激素受体抗体的刺激品种诱导的筏馏分中的多聚体形式的减少。此外，多聚体和单体形式的受体都与Gs α内和外的筏。尽管未能实现总脂筏破坏阻止了关于TSHR信号传导在筏结构域内和没有筏结构域的相对功率的结论，但这些数据清楚地表明，不仅有相当大比例的TSHR驻留在脂质微结构域内，而且TSHR的组成性多聚化实际上在脂筏内受到调节。
The TSH receptor (TSHR), a heptahelical G protein-coupled receptor on the surface of thyrocytes, is a major autoantigen and physiological regulator of the thyroid gland. Unlike other G protein-coupled receptors, the TSHR undergoes posttranslational cleavage of its ectodomain, leading to the existence of several forms of the receptor on the plasma membrane. We previously hypothesized that to achieve high fidelity and specificity of TSH ligand or TSHR autoantibody signaling, the TSHR may compartmentalize into microdomains within the plasma membrane. In support of this hypothesis we have shown previously that TSHRs reside in GM(1) ganglioside-enriched lipid rafts in the plasma membrane of TSHR-expressing cells. In this study, we further explored the different forms of TSHRs that reside in lipid rafts. We studied both TSHR-transfected cells and rat thyrocytes, using both nondetergent biochemical analyses and receptor-lipid raft colocalization. Using the biochemical approach, we observed that monomeric receptors existed in both raft and nonraft fractions of cell surface in the steady state. We also demonstrated that the multimeric forms of the receptor were preferentially partitioned into the lipid microdomains. Different TSHR forms, including multimers, were dynamically regulated both by receptor-specific and postreceptor-specific modulators. TSH ligand and TSHR antibody of the stimulating variety induced a decrease of multimeric forms in the raft fractions. In addition, multimeric and monomeric forms of the receptor were both associated with Gs alpha within and without the rafts. Although failure to achieve total lipid raft disruption prevented a conclusion regarding the relative power of TSHR signaling within and without the raft domains, these data showed clearly that not only were a significant proportion of TSHRs residing within lipid microdomains but that constitutive multimerization of TSHRs was actually regulated within the lipid rafts.