Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor

Human thyrotropin (TSH), luteotropin (LH), follitropin (FSH), and chorionic gonadotropin are members of the heterodimeric glycoprotein hormone family.The common α subunit forms noncovalent heterodimers with different β subunits.Two novel human glycoprotein hormonelike genes, α2 (A2) and β5 (B5), recently have been identified.Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners.Immunological analyses confirmed the heterodimerization of A2 and B5 in transfected cells and their colocalization in the anterior pituitary.Recombinant A2/B5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human TSH receptors, but not LH and FSH receptors, and showed high affinity to TSH receptors in a radioligand receptor assay.The heterodimer also stimulated cAMP production and thymidine incorporation by cultured thyroid cells and increased serum thyroxine levels in TSH-suppressed rats in vivo.This new heterodimeric glycoprotein hormone was named as thyrostimulin based on its thyroid-stimulating activity.The expression of thyrostimulin in the anterior pituitary known to express TSH receptors suggested a paracrine mechanism.The present discovery of a new ligand based on genomic approaches could facilitate the understanding of the physiological roles of extra-thyroid TSH receptor systems and the structural-functional basis of receptor signaling by related glycoprotein hormones.