The seven transmembrane α-helix structure of a G protein-coupled receptor such as FSHR
The FSHR consists of 695 amino acids and has a molecular mass of about 76 kDa.[5] Like other GPCRs, the FSH-receptor possesses seven membrane-spanning domains ortransmembrane helices.
Theextracellular domain of the receptor contains 11 leucine-rich repeats and isglycosylated. It has two subdomains, a hormone-binding subdomain followed by a signal-specificity subdomain.[6] The hormone-binding subdomain is responsible for the high-affinity hormone binding, and the signal-specificity subdomain, containing a sulfated tyrosine at position 335 (sTyr) in a hinge loop, is required for the hormone activity.[7]
Thetransmembrane domain contains two highly conservedcysteine residues that builddisulfide bonds to stabilize the receptor structure. A highly conserved Asp-Arg-Tyr triplet motif is present in GPCR family members in general and may be of importance to transmit the signal. In FSHR and its closely related otherglycoprotein hormone receptor members (LHR andTSHR), this conserved triplet motif is a variation Glu-Arg-Trp sequence.[8]
Upon initial binding to the LRR region of FSHR, FSH reshapes its conformation to form a new pocket. FSHR then inserts its sulfotyrosine from the hinge loop into the pockets and activates the 7-helical transmembrane domain.[6] This event leads to atransduction of the signal that activates theGs protein that is bound to the receptor internally. With FSH attached, the receptor shiftsconformation and, thus, mechanically activates the G protein, which detaches from the receptor and activates thecAMP system.[9][10]
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of FSH to the receptor shifts the equilibrium between active and inactive receptors. FSH and FSH-agonists shift the equilibrium in favor of active states; FSH antagonists shift the equilibrium in favor of inactive states.
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the Gs protein (that was activated by the FSH-receptor) viaadenylate cyclase andcyclic AMP (cAMP).[9][10]
These protein kinases are present astetramers with two regulatory units and two catalytic units. Upon binding of cAMP to the regulatory units, the catalytic units are released and initiate the phosphorylation of proteins, leading to the physiologic action. The cyclic AMP-regulatory dimers are degraded byphosphodiesterase and release 5'AMP.DNA in thecell nucleus binds to phosphorylated proteins through thecyclic AMP response element (CRE), which results in the activation ofgenes.[5]
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified byprostaglandins. Other cellular regulators are participate are the intracellular calcium concentration modified byphospholipase,nitric acid, and other growth factors.
Upregulation refers to the increase in the number of receptor sites on the membrane. Estrogen upregulates FSH receptor sites. In turn, FSH stimulatesgranulosa cells to produceestrogens. This synergistic activity of estrogen and FSH allows for follicle growth and development in the ovary.[citation needed]
The FSHR become desensitized when exposed to FSH for some time. A key reaction of this downregulation is thephosphorylation of the intracellular (orcytoplasmic) receptor domain byprotein kinases.[15] This process uncouples Gs protein from the FSHR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.[citation needed]
Downregulation refers to the decrease in the number of receptor sites. This can be accomplished by metabolizing bound FSHR sites. The bound FSH-receptor complex is brought by lateral migration to a "coated pit," where such units are concentrated and then stabilized by a framework ofclathrins. A pinched-off coated pit is internalized and degraded bylysosomes. Proteins may be metabolized or the receptor can be recycled.
Women with 46XX gonadal dysgenesis experience primaryamenorrhea with hypergonadotropichypogonadism. There are forms of 46 xx gonadal dysgenesis wherein abnormalities in the FSH-receptor have been reported and are thought to be the cause of the hypogonadism.[17]
Polymorphism may affect FSH receptor populations and lead to poorer responses in infertile women receiving FSH medication forIVF.[18]
Alternative splicing of the FSHR gene may be implicated in subfertility in males[19]
^La Marca A, Carducci Artenisio A, Stabile G, Rivasi F, Volpe A (Dec 2005). "Evidence for cycle-dependent expression of follicle-stimulating hormone receptor in human endometrium".Gynecological Endocrinology.21 (6):303–6.doi:10.1080/09513590500402756.hdl:11380/3009.PMID16390776.S2CID24690912.
^Manna PR, Pakarainen P, Rannikko AS, Huhtaniemi IT (November 1998). "Mechanisms of desensitization of follicle-stimulating hormone (FSH) action in a murine granulosa cell line stably transfected with the human FSH receptor complementary deoxyribonucleic acid".Molecular and Cellular Endocrinology.146 (1–2):163–176.doi:10.1016/S0303-7207(98)00156-7.PMID10022774.
^Delbaere A, Smits G, De Leener A, Costagliola S, Vassart G (Apr 2005). "Understanding ovarian hyperstimulation syndrome".Endocrine.26 (3):285–90.doi:10.1385/ENDO:26:3:285.PMID16034183.S2CID7607365.
