Abstract
Follicle-stimulating hormone receptor (FSHR) is a leucine-rich repeat containing class A G-protein coupled receptor belonging to the subfamily of glycoprotein hormone receptors (GPHRs), which includes luteinizing hormone/choriogonadotropin receptor (LH/CGR) and thyroid-stimulating hormone receptor. Its cognate ligand, follicle-stimulating hormone binds to, and activates FSHR expressed on the surface of granulosa cells of the ovary, in females, and Sertoli cells of the testis, in males, to bring about folliculogenesis and spermatogenesis, respectively. FSHR contains a large extracellular domain (ECD) consisting of leucine-rich repeats at the N-terminal end and a hinge region at the C-terminus that connects the ECD to the membrane spanning transmembrane domain (TMD). The TMD consists of seven α-helices that are connected to each other by means of three extracellular loops (ELs) and three intracellular loops (ILs) and ends in a short-cytoplasmic tail. It is well established that the ECD is the primary hormone binding domain, whereas the TMD is the signal transducing domain. However, several studies on the ELs and ILs employing site directed mutagenesis, generation of chimeric receptors and in vitro characterization of naturally occurring mutations have proven their indispensable role in FSHR function. Their role in every phase of the life cycle of the receptor like post translational modifications, cell surface trafficking, hormone binding, activation of downstream signaling, receptor phosphorylation, hormone–receptor internalization, and recycling of hormone–receptor complex have been documented. Mutations in the loops causing dysregulation of these processes lead to pathophysiological conditions. In other GPHRs as well, the loops have been convincingly shown to contribute to various aspects of receptor function. This review article attempts to summarize the extensive contributions of FSHR loops and C-terminal tail to its function.
Highlights
The ability of all organisms to receive external stimuli in the form of light, water, sound, hormones, odors, to name a few, is essential to bring about a necessary physiological response
The delta group consists of the glycoprotein hormone receptors (GPHRs), namely, the follicle-stimulating hormone receptor (FSHR), luteinizing hormone/choriogonadotropin receptor (LH/CGR), and thyroid-stimulating hormone receptor (TSHR)
This study showed that most of the FSH–FHSR complex gets recycled back to the cell surface and truncation of eight residues from the C-tail reroute a substantial portion of the internalized FSH–FSHR complex to a degradation pathway
Summary
The ability of all organisms to receive external stimuli in the form of light, water, sound, hormones, odors, to name a few, is essential to bring about a necessary physiological response This process is mediated through cell surface receptors, mainly the G-protein coupled receptors (GPCRs), which form the largest and most diverse class of receptors. The glycoprotein hormones include the gonadotropins, follicle-stimulating hormone (FSH), luteinizing hormone (LH), the placental hormone chorionic gonadotropin (CG), and the non-gonadotropin thyroid-stimulating hormone (TSH) They belong to the cystine-knot growth factor superfamily and share a common heterodimeric structure composed of two non-covalently associated α and β subunits [6]. A few relevant examples from studies on the loops of LH/CGR and TSHR have been cited
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