Intracellular Trafficking of Gonadotropin Receptors in Health and Disease.

Gonadotropin receptors belong to the highly conserved subfamily of the G protein-coupled receptor (GPCR) superfamily, the so-called Rhodopsin-like family (class A), which is the largest class of GPCRs and currently a major drug target. Both the follicle-stimulating hormone receptor (FSHR) and the luteinizing hormone/chorionic gonadotropin hormone receptor (LHCGR) are mainly located in the gonads where they play key functions associated to essential reproductive functions. As any other protein, gonadotropin receptors must be properly folded into a mature tertiary conformation compatible with quaternary assembly and endoplasmic reticulum export to the cell surface plasma membrane. Several primary and secondary structural features, including presence of particular amino acid residues and short motifs and in addition, posttranslational modifications, regulate intracellular trafficking of gonadotropin receptors to the plasma membrane as well as internalization and recycling of the receptor back to the cell surface after activation by agonist. Inactivating mutations of gonadotropin receptors may derive from receptor misfolding and lead to absent or reduced plasma membrane expression of the altered receptor, thereby manifesting an array of phenotypical abnormalities mostly characterized by reproductive failure and/or abnormal or absence of development of secondary sex characteristics. In this chapter we review the structural requirements necessary for intracellular trafficking of the gonadotropin receptors, and describe how mutations in these receptors may lead to receptor misfolding and disease in humans.