The luteinizing hormone receptor

Abstract

Both major and incremental advances in the past decade have provided important insights into the structure, function, and regulation of the luteinizing hormone receptor (LHR) and its gene. The availability of the crystal structure of the extracellular domain of the follicular stimulating hormone receptor-hormone complex, and its applicability to other members of the gonadotropin receptor family, has facilitated prediction of the localized areas of specific interaction between the LHR and its cognate hormone. This has been supported by the incorporation of information derived from mutational and chimeric studies. The nature of the structural and molecular changes involved in the initiation and propagation of signaling is beginning to be revealed by the various models. It is likely that components of each domain of the LHR, the hinge region of the extracellular domain, and the LH/human chorionic gonadotrophin α-1,3 loops participate in the receptor activation. Naturally occurring and created mutations have provided fertile ground for modeling, leading to plausible proposals for the regions of the receptor that participate in receptor coupling functions. The knockout mouse model has demonstrated the lack of participation of the hormone/receptor in fetal gonadal development, in contrast with the situation in the human, where the essentiality of the LHR is exemplified by Leydig cell hypoplasia. The association of an LHR polymorphism with breast cancer age of onset and severity has been documented. Significant advances have been achieved in studies on LHR gene structure and regulation of transcription. Two independent mechanism of repression/derepression have been identified. Studies on the epigenetic control of LHR transcription have revealed the combined importance of promoter methylation status; and changes in histone acetylation/methylation in the association/release of inhibitory complexes from the promoter, and recruitment of the preinitiation complex and polymerase II. Furthermore, major advances await elucidation of the participation and molecular mechanisms of signaling pathways involved in the transcription of the LHR.