Multiple mechanisms of allosteric regulation of the luteninizing hormone receptor

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Дәйексөз келтіру

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Рұқсат жабық Тек жазылушылар үшін

Аннотация

The regulatory effects of luteinizing hormone (LH) and chorionic gonadotropin (CG) are realized through the activation of the G-protein coupled LH/CG receptor (LH/CG-R). The result of this is the activation of various types of G proteins, which leads to stimulation (Gs) or inhibition (Gi) of the cAMP-dependent pathway and stimulation of calcium signaling (Gq/11, Gi), and the recruitment of β-arrestins, which prevent G protein signaling through receptor internalization and downregulation, but can also activate the mitogen-activated protein kinase cascade. Despite a certain similarity in the effects of LH and CG, there are differences between them both in efficiency and in the pattern of regulation of LH/CG-R. This is a consequence of differences in the affinity of LH and CG to the orthosteric site of the receptor, as well as differences at the level of allosteric regulation of the receptor, which is due to the presence of a C-terminal extension in the β-subunit of CG, including sites for O-glycosylation, and the variability of N-glycosylation of α- and β-subunits of gonadotropins. Moreover, the number of N-glycans, the degree of their branching and charge differ, which leads to different efficiency of activation of intracellular cascades, affecting the physiological response of the reproductive system to gonadotropins. Of great importance is the formation of homodi(oligo)meric complexes of LH/CG-R and its heterocomplexes with the follicle-stimulating hormone receptor, where protomers allosterically influence the efficiency of LH/CG-R activation and the bias of signal transduction. Taking into account the large number of allosteric sites in LH/CG-R, the development of low-molecular allosteric regulators is underway, including agonists based on thieno[2,3-d]-pyrimidine and peptides derived from the cytoplasmic loops of LH/CG-R. These regulators can become prototypes of drugs for correcting the functions of the reproductive system. This review is devoted to the analysis of data on the similarities and differences in the signaling and physiological effects of gonadotropins with LH activity, the role of allosteric mechanisms in this, and the prospects for creating allosteric regulators of LH/CG-R.

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Авторлар туралы

A. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Хат алмасуға жауапты Автор.
Email: alex_shpakov@list.ru
Ресей, St. Petersburg, 194223

K. Derkach

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: derkatch_k@list.ru
Ресей, St. Petersburg, 194223

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2. Fig. 1. N- and O-glycosylation of subunits of human LH and hCG, as well as FSH presented for comparison. For α-LH, α-FSH and α-CG, glycoforms of α-subunits characteristic of LH, FSH and placental hCG molecules are presented. Sites for N-glycosylation are shown in all subunits, and in β-subunits of hCG, sites for O-glycosylation also localized in the C-terminal part of the molecules are shown. The most typical structures of N-glycans characteristic of the presented gonadotropins are shown. In the α- and β-subunits of LH and hCG, weakly branched (hybrid and biantennary) N-glycans predominate, with LH secreted by the pituitary gland containing more sulfated N-acetylgalactosamine (GalNAc), and in hCG secreted by the fetus and placenta, sialic acid residues predominate. In the α- and β-subunits of FSH, there is a significant number of more branched (three- and four-antennary) N-glycans enriched in sialic acid. Terminal sialic acid residues are shown as open squares, terminal sulfated GalNAc residues are shown as filled circles.

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3. Fig. 2. Signaling pathways realized through LH/hCG-R, as well as endosomal signaling carried out with the participation of gonadotropin-bound LH/hCG-R. Designations: LH/hCG-R – LH and hCG receptor; AC – adenylate cyclase; cAMP – 3’-5’-cyclic adenosine monophosphate; PKA – protein kinase A; PDE4,7,8 – cAMP-activated phosphodiesterases types 4, 7 and 8; Epac1/2 – exchange proteins types 1 and 2, activated by cyclic AMP; Gs, Gi, Gq/11 – αβγ-heterotrimeric proteins that stimulate (Gs) or inhibit (Gi) AC and activate calcium signaling (Gq/11); β-App – β-arrestin; ERK1/2 – extracellular signal-regulated kinases types 1 and 2; PLCβ – phosphoinositide-specific phospholipase Cβ; DAG – diacylglycerol; IP3 – inositol-3,4,5-triphosphate; [Ca2+]i – intracellular Ca2+ concentration; PKC – phorbol-sensitive protein kinase C isoforms.

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