Thyrotropin receptor mutations as a tool to understand thyrotropin receptor action

作     者：Wonerow, P Neumann, S Gudermann, T Paschke, R 

作者机构：Univ Leipzig Med Klin D-04103 Leipzig Germany Univ Marburg Fachbereich Humanmed Inst Pharmakol & Toxikol D-35033 Marburg Germany 

出 版 物：《JOURNAL OF MOLECULAR MEDICINE-JMM》 (分子医学杂志)

年 卷 期：2001年第79卷第12期

页      面：707-721页

核心收录：

学科分类：0710[理学-生物学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

主　　题：thyrotropin receptor mutations site-directed mutagenesis structure-function relationships 

摘      要：A large number of mutations have been identified in the thyrotropin (TSH) receptor (TSHR) gene causing human diseases. Toxic thyroid nodules are frequently associated with somatic constitutively activating TSHR mutations. Autosomal dominant nonautoimmune hyperthyroidism is caused by activating TSHR germline mutations. Inactivating germline mutations cause TSH unresponsivness. Discovery of the different TSHR mutations in various regions of the receptor molecule has led to the identification of important domains for intramolecular TSHR signal transduction. However, despite the functional characterization of the naturally occurring mutations the precise molecular mechanisms of receptor activation including the processes of hormone binding, intramolecular signaling between the different TSHR domains and of G protein coupling are not completely understood. This review discusses the importance of the various receptor domains for TSHR activation identified on the basis of the naturally occurring gain or loss of function mutations and in vitro investigations performed with site-directed mutagenesis, synthetic peptides, or antibodies. Several in vitro studies have provided new insights into structure-function relationships by site-directed mutagenesis in combination with molecular modeling. These in vitro investigations have often been guided by naturally occurring mutations and have provided new insights into intramolecular changes during receptor activation. This has led to progress in understanding the mechanism of TSHR activation.