G-protein-coupled receptors (GPCR) are receptors that represent a large class of cell membrane proteins involved in 80% of signaling through the plasma membrane of our cells. Compounds that bind to and activate these receptors include hormones, neurotransmitters, pheromones, photosensitive molecules, and other factors in the regulation of critical physiological processes. The disruption of G-protein coupled receptors leads to a variety of diseases, whereas the receptors themselves are targeted by about 40 percent of all drugs currently produced. Robert Lefkowitz and Brian Kobilka were awarded the Nobel Prize in Chemistry in 2012 for the research of receptors associated with G-protein (2).
G-proteins of biological membranes have a heterotrimeric structure. They consist of a large ? subunit (about 45 kDa), as well as smaller ? and ? subunits. In the unstimulated state of the ? subunit the G-protein is inactive, but once it’s activated, ? subunit releases its bound GDP, allowing GTP to bind in its place. GTP binding then causes an activating conformational change in the G? subunit, releasing the G protein from the receptor and triggering dissociation of the GTP-bound G? subunit from the G?? pair. In the inactive state, the ?? complex is weakly bound to the ? subunit. The ? subunit is linked to the biological membrane by the geranyl-geranyl chain close in structure to cholesterol. The ? subunit is also bound to the membrane by a fatty acid with a chain length of 14 carbon atoms (myristic acid). Such bonds allow G-proteins to be mobile inside a cell, shuttling continually between the plasma membrane and intracellular membranes in the basal state. Furthermore, ?? subunits translocate rapidly and reversibly to the Golgi and endoplasmic reticulum enabling direct communication between the extracellular signal and intracellular membranes (1).
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a genetically determined disease characterized by a triad of symptoms: the presence of café au lait skin macules – “coffee and milk” spots on the skin, fibrous dysplasia of bones, and various endocrinopathies (the most common one is premature sexual development).
FD/MAS is a result of a mutation in the GNAS1 gene encoding the ? subunit of the guanidine triphosphate binding protein (G-protein), which stimulates the formation of cAMP. The latter, among other processes, regulates many endocrine glands of the body. Mutant protein constantly activates adenylate cyclase, intracellular level of cAMP increases, which leads to spontaneous “inclusion” of hormone secretion. GNAS1 is located on the long arm of the 20th chromosome. This cell mutation occurs in the early stages of embryogenesis, during the first 10 weeks of pregnancy. In this case, the mutation is not localized in all cells of the body, but only in individual clones of the mutant cell. Consequently, the earlier in the process of embryonic development a mutation occurs, the more cells will have a structural defect, and the more clinical manifestations the disease will have. Activation of the ? subunit of the G-protein and an increase in the intracellular level of cAMP are underlying causes of the FD/MAS symptoms. The synthesis of melanin and its transport into epithelial cells are stimulated by melanostimulating hormone and ACTH. Receptors of these hormones use cAMP as an intermediary. When the levels of cAMP are increased, the production of melanin increases as well, although the levels of ACTH and melanostimulating hormone are normal. This explains the presence of hyperpigmentation spots on the skin. Activation of the synthesis of estrogens occurs the same way – without the involvment of gonadotropins. This leads to the formation of follicular ovarian cysts and gonadotropin-independent premature puberty. In addition, cAMP is involved in the differentiation of osteoblasts in bone tissue. It is believed that uncontrolled activation of osteoblasts due to the mutation in the GNAS1 gene promotes the development of fibrotic dysplasia in individuals with FD/MAS (3).
Treatment of FD/MAS is aimed at relieving the symptoms of the disease and requires individual approach since the prevalence of symptoms differ. Multidisciplinary team of specialists – pediatricians, endocrinologists, orthopedists, surgeons, gynecologists, neurologists, etc. – is needed for an effective management of the disease. Conservative therapy of fibrous dysplasia with bisphosphonates such as pamidronic acid, alendronic acid, zoledronic acid, etc. is used. Bisphosphonates are synthetic analogues of natural pyrophosphates, they form a bone matrix and inhibit bone resorption.
Surgeries might be required for the correction of the limbs due to their deformation and shortening. Medroxyprogesterone acetate is used to treat premature sexual development. In individuals with severe bone damage this drug should be used carefully, since it causes hypocalcemia.