[A study on the role of the transmembrane V to VI regions of the human luteinizing hormone receptor in its constitutive activation].
Gonadotropin (luteinizing hormone: LH, and follicle stimulating hormone: FSH) receptors are members of the seven-transmembrane (TM) receptor family. Recently, point mutations have been identified in the LH receptor gene, leading to constitutive activation (ligand-independent activation) of the receptor in patients with familial male-limited precocious puberty. Most of such point mutations were found in the coding region consisting of TM V, VI and the intracellular loop 3 (i3). Because the primary structures of gonadotropin receptors are highly conserved, in vitro mutagenesis was performed to introduce the amino acid substitution in the i3 domain (Asp-->Gly) of FSH receptor, corresponding to the point mutation leading to constitutive activation in LH receptor. However, the FSH receptor mutant showed almost similar basal cAMP production to wild type counterpart. For investigation of this difference in constitutive activation between two receptors, the author designed chimeric LH/FSH receptors with or without an amino acid substitution in the i3 (Asp-->Gly) to identify the region in the LH receptor which is important for its constitutive activation. Introduction of the amino acid substitution into a chimeric receptor containing only TM V to VI from the LH receptor led to major increases in ligand-independent cAMP production. Furthermore, the chimeric receptor with only TM V and VI derived from the LH receptor was constitutively activated by the amino acid substitution in the i3 from the FSH receptor. These results that interactions between TM V and VI of the FSH receptor are essential for maintaining the receptor conformation constrained, whereas interactions between these domains of the LH receptor are required for constitutive activation by the amino acid substitution in the i3.
D000818:Animals; D002678:Chimera; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008024:Ligands; D017354:Point Mutation; D011962:Receptors, FSH / Q000235:genetics*; D011974:Receptors, LH / Q000235:genetics*