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Novel Insights into the Molecular Mechanisms of Human Thyrotropin Action: Structural, Physiological, and Therapeutic Implications for the Glycoprotein Hormone Family

Laboratory of Molecular Endocrinology, Department of Medicine, University of Maryland School of Medicine and the Institute of Human Virology, Medical Biotechnology Center, Baltimore, Maryland 21201

I. Introduction A. Historical background

B. TSH and the glycoprotein hormone family

II. Structure-Function Relationships of TSH in Relation to Studies on Gonadotropins

A. Methodological considerations

B. Structure-function studies of protein domains

C. Structure-function studies of carbohydrate chains

III. Current Understanding of TSH/Glycoprotein Hormone Action

A. Structural considerations

B. Hormone-receptor interaction

C. Cooperation of individual hTSH domains in receptor activation

IV. Physiological and Pathophysiological Implications

A. Carbohydrate heterogeneity

B. Naturally occurring glycoprotein hormone mutations

C. "Specificity spillover" syndromes

V. Evolutionary Considerations

A. Glycoprotein hormone specificity

B. Evolutionary changes in TSH activity

VI. Strategies in the Design of Novel TSH Analogs and Therapeutic Implications

A. Clinical use of rhTSH

B. Design of novel glycoprotein hormone analogs

VII. Nonclassic Actions of TSH and Gonadotropins

A. Extrathyroidal/extragonadal glycoprotein hormone actions

B. Relationship to the cystine knot growth factor superfamily

VIII. Perspectives on Structure-Function Studies of TSH