Endocrine Regulation of Male Fertility by the Skeleton

Oury, Franck; Sumara, Grzegorz; Sumara, Olga; Ferron, Mathieu; Chang, Haixin; Smith, Charles E.; Hermo, Louis; Suárez, Susan S.; Roth, Bryan L.; Ducy, Patricia; Karsenty, Gérard

doi:10.1016/j.cell.2011.02.004

Cited by 551 publications

(668 citation statements)

References 63 publications

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“…Because these key data were reproduced with three distinct mGlu receptors, the proposed mechanism is likely general to all class C GPCRs containing a CRD, then including the sweet and umami taste receptors (31), the CaSR (32), and the GPRC6a recently shown to be involved in the effect of osteocalcin (33).…”

Section: Discussionmentioning

confidence: 99%

Interdomain movements in metabotropic glutamate receptor activation

Huang

Cao

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Many cell surface receptors are multimeric proteins, composed of several structural domains, some involved in ligand recognition, whereas others are responsible for signal transduction. In most cases, the mechanism of how ligand interaction in the extracellular domains leads to the activation of effector domains remains largely unknown. Here we examined how the extracellular ligand binding to the venus flytrap (VFT) domains of the dimeric metabotropic glutamate receptors activate the seven transmembrane (7TM) domains responsible for G protein activation. These two domains are interconnected by a cysteine-rich domain (CRD). We show that any of the four disulfide bridges of the CRD are required for the allosteric coupling between the VFT and the 7TM domains. More importantly, we show that a specific association of the two CRDs corresponds to the active state of the receptor. Indeed, a specific crosslinking of the CRDs with intersubunit disulfide bridges leads to fully constitutively active receptors, no longer activated by agonists nor by allosteric modulators. These data demonstrate that intersubunit movement at the level of the CRDs represents a key step in metabotropic glutamate receptor activation.transmembrane signaling | G protein-coupled receptor | allosteric modulation M ost cell surface receptors are multimeric complexes of which each subunit is produced through the association of different domains throughout evolution (1-5). The activation of such receptor complexes is a result of coordinated conformational changes or movement of these different domains. Although an increasing amount of 3D crystal structures are becoming available, there is still limited information available on the structural basis of interdomain communication.Class C G protein-coupled receptors (GPCRs) represent key examples of such receptor complexes (6, 7). These receptors are obligatory dimers, either homo-or heterodimers, made by the association of two domains over evolutionary time; an extracellular bilobate venus flytrap (VFT) domain associated with a G protein activating 7 transmembrane (7TM) domain (Fig. 1A) (8). The VFTs are evolved from certain types of bacterial periplasmic binding proteins, especially those of the leucine-isoleucinevaline binding protein family involved in the transport of amino acids, sugars, or ions. Not surprisingly, class C GPCRs are activated by amino acids, i.e., the receptors for the two major neurotransmitters, the eight metabotropic glutamate receptors (mGluRs), and the GABA B receptor; sugar (the sweet taste receptors); or ions [the calcium-sensing receptor (CaSR)]. Accordingly, class C GPCRs represent exciting new targets for drug development for both the pharmaceutical and food industries, as illustrated by the number of drugs targeting these receptors already on the market (the GABA B receptor agonist baclofen, umami compounds, and various sweeteners such as aspartame, and cinacalcet, a positive allosteric modulator of the CaSR), and those in clinical trials (9-11).The precise mechanisms of how...

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Section: Discussionmentioning

confidence: 99%

Interdomain movements in metabotropic glutamate receptor activation

Huang

Cao

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Additional mechanisms include the impairment of vitamin D‐dependent osteocalcin production81 and the altered Wnt signalling in osteoblasts and osteocytes observed in CKD,82 which is associated with bone loss and vascular calcification 83, 84. As vitamin D inhibits the adverse TGFβ/Smad action on bone cells, a normal vitamin D status might provide protection against Wnt signalling‐related bone loss in CKD 85…”

Section: Vitamin D Metabolism In Chronic Kidney Diseasementioning

confidence: 99%

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

Molina

Carrero

Bover

et al. 2017

J cachexia sarcopenia muscle

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The spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non‐genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25‐hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions.

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“…On the other hand, long term warfarin anticoagulation almost did not affect serum OC. Circulating undercarboxylated OC was described to be able to stimulate secretion of insulin and to increase tissues susceptibility to insulin (7,8) and to influence male fertility (38). During long term anticoagulation therapy in human, modifications of glucose homeostasis or fertility were not reported.…”

mentioning

confidence: 99%

VKORC1L1, an Enzyme Rescuing the Vitamin K 2,3-Epoxide Reductase Activity in Some Extrahepatic Tissues during Anticoagulation Therapy

Hammed

Matagrin

Spohn

et al. 2013

Journal of Biological Chemistry

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Background: Effective involvement of VKORC1L1 in vitamin K epoxide reductase activity, target of vitamin K antagonists (VKAs), is still unclear. Results: VKORC1L1 is not inhibited by VKAs and catalyzes VKOR activity in extrahepatic tissues. Conclusion: During long term anticoagulation the limited unwanted side effects of VKAs are due to VKORC1L1. Significance: Potential pharmaco-toxicologic effects of specific VKORC1L1 inhibitors should be assessed.

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Endocrine Regulation of Male Fertility by the Skeleton

Cited by 551 publications

References 63 publications

Interdomain movements in metabotropic glutamate receptor activation

Interdomain movements in metabotropic glutamate receptor activation

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

VKORC1L1, an Enzyme Rescuing the Vitamin K 2,3-Epoxide Reductase Activity in Some Extrahepatic Tissues during Anticoagulation Therapy

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