Abstract Background GPRC6A, a widely expressed G-protein coupled receptor, is proposed to be a master regulator of complex endocrine networks and metabolic processes. GPRC6A is activated by multiple ...ligands, including osteocalcin (Ocn), testosterone (T), basic amino acids, and various cations. Scope of Review We review the controversy surrounding GPRC6A functions. In mice, GPRC6A is proposed to integrate metabolic functions through the coordinated secretion of hormones, including insulin, GLP-1, T, and IL-6, and direct effects of this receptor to control glucose and fat metabolism in the liver, skeletal muscle, and fat. Loss-of-GPRC6A results in metabolic syndrome (MetS), and activation of GPRC6A stimulates proliferation of β-cells, increases peripheral insulin sensitivity, and protects against high fat diet (HFD) induced metabolic abnormalities in most mouse models. Bone, cardiovascular, immune, and skin functions of GPRC6A have also been identified in mice. Expression of GPRC6A is increased in prostate cancer (PCa) cells, and inhibition of GPRC6A attenuates PCa progression in mouse models. The function of GPRC6A in humans, however, is not clear. During evolution, a unique polymorphism of GPRC6A emerged mainly in humans of Asian and European decent that has been proposed to alter membrane trafficking and function. In contrast, the ancestral allele found in all other species is retained in 1%, 15%, and 40% of people of Asian, European and African descent, respectively, suggesting GPRC6A gene variants may contribute to the racial disparities in the risk of developing MetS and PCa. Major Conclusions If the regulatory functions of GPRC6A identified in mice translate to humans, and polymorphisms in GPRC6A are found to predict racial disparities in human diseases, GPRC6A may be a new gene target to predict, prevent, and treat MetS, PCa, and other disorders impacted by GPRC6A.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Structural asymmetry in FGF23 signaling Liu, Shih-Hsien; Xiao, Zhousheng; Smith, Jeremy C ...
Trends in pharmacological sciences (Regular ed.),
12/2023, Volume:
44, Issue:
12
Journal Article
Peer reviewed
Chen et al. have derived cryogenic electron microscopy (cryo-EM) structures of signaling complexes of the endocrine hormone fibroblast growth factor 23 (FGF23) with fibroblast growth factor receptor ...(FGFR), α-Klotho, and heparin sulfate. These structures are asymmetric, leading to questions concerning in vivo function, and will facilitate structure-based drug design to modulate FGF23 signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pkd1 localizes to primary cilia in osteoblasts and osteocytes. Targeted deletion of Pkd1 in osteoblasts results in osteopenia and abnormalities in Runx2-mediated osteoblast development. Kif3a, an ...intraflagellar transport protein required for cilia function, is also expressed in osteoblasts. To assess the relationship between Pkd1 and primary cilia function on bone development, we crossed heterozygous Pkd1- and Kif3a-deficient mice to create compound Pkd1 and Kif3a-deficient mice. Pkd1 haploinsufficiency (Pkd1(+/Δ)) resulted in osteopenia, characterized by decreased bone mineral density, trabecular bone volume, and cortical thickness. In addition, deficiency of Pkd1 resulted in impaired osteoblastic differentiation and enhanced adipogenesis in both primary osteoblasts and/or bone marrow stromal cell cultures. These changes were associated with decreased Runx2 expression, increased PPARγ expression, and impaired hedgehog signaling as evidenced by decreased Gli2 expression in bone and osteoblast cultures. In contrast, heterozygous Kif3a(+/Δ) mice display no abnormalities in skeletal development or osteoblast function, but exhibited decreased adipogenic markers in bone and impaired adipogenesis in vitro in association with decreased PPARγ expression and upregulation of Gli2. Superimposed Kif3a deficiency onto Pkd1(+/Δ) mice paradoxically corrected the effects of Pkd1 deficiency on bone mass, osteoblastic differentiation, and adipogenesis. In addition, Runx2, PPARγ and Gli2 expression in bone and osteoblasts were normalized in compound double Pkd1(+/Δ) and Kif3a(+/Δ) heterozygous mice. The administration of sonic hedgehog, overexpression of Gli2, and the PC1 C-tail construct all increased Gli2 and Runx2-II expression, but decreased PPARγ2 gene expression in C3H10T1/2 cells. Our findings suggest a role for Pkd1 and Kif3a to counterbalance the regulation of osteogenesis and adipogenesis through differential regulation of Runx2 and PPARγ by Gli2.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
G protein-coupled receptor family C group 6 member A (GPRC6A) is activated by testosterone and modulates prostate cancer progression. Most humans have a GPRC6A variant that contains a recently ...evolved KGKY insertion/deletion in the third intracellular loop (ICL3) (designated as GPRC6A
) that replaces the ancestral KGRKLP sequence (GPRC6A
) present in all other species. In vitro assays purport that human GPRC6A
is retained intracellularly and lacks function. These findings contrast with ligand-dependent activation and coupling to mammalian target of rapamycin complex 1 (mTORC1) signaling of endogenous human GPRC6A
in PC-3 cells. To understand these discrepant results, we expressed mouse (mGPRC6A
), human (hGPRC6A
), and humanized mouse (mGPRC6A
) GPRC6A into human embryonic kidney 293 cells. Our results demonstrate that mGPRC6A
acts as a classic G protein-coupled receptor, which is expressed at the cell membrane and internalizes in response to ligand activation by testosterone. In contrast, hGPRC6A
and humanized mouse mGPRC6A
are retained intracellularly in ligand naive cells, yet exhibit
-arrestin-dependent signaling responses, mitogen-activated protein kinase i.e., extracellular signal-regulated kinase (ERK), and p70S6 kinase phosphorylation in response to testosterone, indicating that hGPRC6A
is functional. Indeed, testosterone stimulates time- and dose-dependent activation of ERK, protein kinase B, and mTORC1 signaling in wild-type PC-3 cells that express endogenous GPRC6A
In addition, testosterone stimulates GPRC6A-dependent cell proliferation in wild-type PC-3 cells and inhibits autophagy by activating mTORC1 effectors eukaryotic translation initiation factor 4E binding protein 1 and Unc-51 like autophagy activating kinase 1. Testosterone activation of GPRC6A has the obligate requirement for calcium in the incubation media. In contrast, in GPRC6A-deficient cells, the effect of testosterone to activate downstream signaling is abolished, indicating that human GPRC6A is required for mediating the effects of testosterone on cell proliferation and autophagy.
We investigated whether Kif3a in osteoblasts has a direct role in regulating postnatal bone formation. We conditionally deleted Kif3a in osteoblasts by crossing osteocalcin (Oc; also known as ...Bglap)-Cre with Kif3a(flox/null) mice. Conditional Kif3a-null mice (Kif3a(Oc-cKO)) had a 75% reduction in Kif3a transcripts in bone and osteoblasts. Conditional deletion of Kif3a resulted in the reduction of primary cilia number by 51% and length by 27% in osteoblasts. Kif3a(Oc-cKO) mice developed osteopenia by 6 weeks of age unlike Kif3a(flox/+) control mice, as evidenced by reductions in femoral bone mineral density (22%), trabecular bone volume (42%) and cortical thickness (17%). By contrast, Oc-Cre;Kif3a(flox/+) and Kif3a(flox/null) heterozygous mice exhibited no skeletal abnormalities. Loss of bone mass in Kif3a(Oc-cKO) mice was associated with impaired osteoblast function in vivo, as reflected by a 54% reduction in mineral apposition rate and decreased expression of Runx2, osterix (also known as Sp7 transcription factor 7; Sp7), osteocalcin and Dmp1 compared with controls. Immortalized osteoblasts from Kif3a(Oc-cKO) mice exhibited increased cell proliferation, impaired osteoblastic differentiation, and enhanced adipogenesis in vitro. Osteoblasts derived from Kif3a(Oc-cKO) mice also had lower basal cytosolic calcium levels and impaired intracellular calcium responses to fluid flow shear stress. Sonic hedgehog-mediated Gli2 expression and Wnt3a-mediated β-catenin and Axin2 expression were also attenuated in Kif3a(Oc-cKO) bone and osteoblast cultures. These data indicate that selective deletion of Kif3a in osteoblasts disrupts primary cilia formation and/or function and impairs osteoblast-mediated bone formation through multiple pathways including intracellular calcium, hedgehog and Wnt signaling.
Both the activation of the renin angiotensin aldosterone system (RAAS) and elevations of circulating Fibroblast Growth Factor-23 (FGF-23) have been implicated in the pathogenesis of left ventricular ...hypertrophy (LVH) in chronic kidney disease. To investigate potential cross-talk between RAAS and FGF-23, we administered angiotensin II (Ang II) to wild-type rodents and the Hyp mouse model of excess FGF-23. Ang II administration for four weeks to wild-type rodents resulted in significant increases in systolic blood pressure and LVH. Unexpectedly, FGF-23 circulating levels were increased by 1.5-1.7 fold in Ang II treated animals. In addition, Ang II treatment increased expression of FGF-23 message levels in bone, the predominant tissue for FGF-23 production, and induced expression of FGF-23 and its co-receptor α-Klotho in the heart, which normally does not express FGF-23 or α-Klotho in physiologically relevant levels. Hyp mice with elevated FGF-23 exhibited increased blood pressure and LVH at baseline. Ang II administration to Hyp mice resulted further increments in blood pressure and left ventricular hypertrophy, consistent with additive cardiovascular effects. These findings suggest that FGF-23 may participate in unexpected systemic and paracrine networks regulating hemodynamic and myocardial responses.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives The study objective was to assess the association between angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use and mortality in patients with chronic ...kidney disease (CKD). Background There is insufficient evidence about the association of ACEI or ARBs with mortality in patients with CKD. Methods A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 U.S. veterans with nondialysis CKD who were previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores using the Kaplan-Meier method and Cox models in “intention-to-treat” analyses and in generalized linear models with binary outcomes and inverse probability of treatment weights in “as-treated” analyses. Results The age of the patients at baseline was 75 ± 10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with a significantly lower risk of mortality both in the intention-to-treat analysis (hazard ratio: 0.81, 95% confidence interval: 0.78 to 0.84; p < 0.001) and the as-treated analysis with inverse probability of treatment weights (odds ratio: 0.37, 95% confidence interval: 0.34 to 0.41; p < 0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups. Conclusions In this large contemporary cohort of nondialysis-dependent patients with CKD, ACEI/ARB administration was associated with greater survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating ...for ∼5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of ∼4,500 metabolic, physiological, pharmacological and behavioural traits, and more than 90 independent expression quantitative trait locus (QTL), transcriptome, proteome, metagenome and metabolome data sets--by far the largest coherent phenome for any experimental cohort (www.genenetwork.org). We tested downstream effects of subsets of variants and discovered several novel associations, including a missense mutation in fumarate hydratase that controls variation in the mitochondrial unfolded protein response in both mouse and Caenorhabditis elegans, and missense mutations in Col6a5 that underlies variation in bone mineral density in both mouse and human.
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