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GPRC6a

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https://www.readbyqxmd.com/read/28659174/crispr-cas9-targeting-of-gprc6a-suppresses-prostate-cancer-tumorigenesis-in-a-human-xenograft-model
#1
Ruisong Ye, Min Pi, John V Cox, Satoru K Nishimoto, L Darryl Quarles
BACKGROUND: GPRC6A is implicated in the pathogenesis of prostate cancer, but its role remains uncertain because of a purported tolerant gene variant created by substitution of a K..Y polymorphism in the 3rd intracellular loop (IL) that evolved in the majority of humans and replaces the ancestral RKLP present in 40% of humans of African descent and all other species. METHODS: We determined whether the K..Y polymorphism is present in human-derived prostate cancer cell lines by sequencing the region of the 3rd IL and assessed the cellular localization of a "humanized" mouse GPRC6A containing the K...
June 28, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28559246/neprilysin-is-required-for-angiotensin-1-7-s-ability-to-enhance-insulin-secretion-via-its-proteolytic-activity-to-generate-angiotensin-1-2
#2
Gurkirat S Brar, Breanne M Barrow, Matthew Watson, Ryan Griesbach, Edwina Choung, Andrew Welch, Bela Ruzsicska, Daniel P Raleigh, Sakeneh Zraika
Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS...
August 2017: Diabetes
https://www.readbyqxmd.com/read/28428077/molecular-bases-of-the-crosstalk-between-bone-and-muscle
#3
Gerard Karsenty, Paula Mera
Exercise is an evolutionary conserved survival function that nowadays has beneficial health effects. The increased metabolic activity of contracting skeletal muscle affects the biology of many organs involved in regulating muscle functions. The discovery of hormones and cytokines secreted by bone and skeletal muscle during exercise, has recently added experimental credence to the notion that a crosstalk exists between these organs. Bone through the hormone osteocalcin, promotes exercise capacity in the mouse...
April 18, 2017: Bone
https://www.readbyqxmd.com/read/28395130/osteocalcin-a-bone-derived-hormone-with-important-andrological-implications
#4
REVIEW
L De Toni, A Di Nisio, M S Rocca, M De Rocco Ponce, A Ferlin, C Foresta
Increasing evidence disclosed the existence of a novel multi-organ endocrine pathway, involving bone, pancreas and testis, of high penetrance in energy metabolism and male fertility. The main mediator of this axis is undercarboxylated osteocalcin (ucOC), a bone-derived protein-exerting systemic effects on tissues expressing the metabotropic receptor GPRC6A. The recognized effects of ucOC are the improvement of insulin secretion from the pancreas, the amelioration of systemic insulin sensitivity, in particular in skeletal muscle, and the stimulation of the global endocrine activity of the Leydig cell, including vitamin D 25-hydroxylation and testosterone production...
April 10, 2017: Andrology
https://www.readbyqxmd.com/read/28180060/gprc6a-jack-of-all-metabolism-or-master-of-none
#5
REVIEW
Min Pi, Satoru Kenneth Nishimoto, L Darryl Quarles
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...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/27986810/genetic-variations-in-the-human-g-protein-coupled-receptor-class-c-group-6-member-a-gprc6a-control-cell-surface-expression-and-function
#6
Stine Jørgensen, Christian Theil Have, Christina Rye Underwood, Lars Dan Johansen, Petrine Wellendorph, Anette Prior Gjesing, Christinna V Jørgensen, Shi Quan, Gao Rui, Asuka Inoue, Allan Linneberg, Niels Grarup, Wang Jun, Oluf Pedersen, Torben Hansen, Hans Bräuner-Osborne
GPRC6A is a G protein-coupled receptor activated by l-amino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are Gq-coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface-expressed and functional...
January 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27943578/robust-glp-1-secretion-by-basic-l-amino-acids-does-not-require-the-gprc6a-receptor
#7
Christoffer Clemmensen, Christinna V Jørgensen, Sanela Smajilovic, Hans Bräuner-Osborne
The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) has been proposed to be a sensor for basic L-amino acids that are hypothesized to translate ingestive behaviour to endocrine information. However, the contribution of the GPRC6A receptor to L-amino acid-induced glucagon-like peptide 1 (GLP-1) secretion is unclear. Therefore, to discover whether the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands (L-arginine and L-ornithine) and assessed GLP-1 levels in circulation...
December 10, 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27790153/nerve-growth-factor-brain-derived-neurotrophic-factor-and-osteocalcin-gene-relationship-in-energy-regulation-bone-homeostasis-and-reproductive-organs-analyzed-by-mrna-quantitative-evaluation-and-linear-correlation-analysis
#8
Claudia Camerino, Elena Conte, Maria Cannone, Roberta Caloiero, Adriano Fonzino, Domenico Tricarico
Nerve Growth Factor (NGF)/Brain-derived Neurotrophic Factor (BDNF) and osteocalcin share common effects regulating energy, bone mass, reproduction and neuronal functions. To investigate on the gene-relationship between NGF, BDNF, and Osteocalcin we compared by RT-PCR the transcript levels of Ngf, Bdnf and Osteocalcin as well as of their receptors p75NTR/NTRK1, NTRK2, and Gprc6a in brain, bone, white/brown adipose tissue (WAT/BAT) and reproductive organs of 3 months old female and male mice. Brain and bone were used as positive controls for NGF/BDNF and Osteocalcin respectively...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27760167/genomic-regions-associated-with-feed-efficiency-indicator-traits-in-an-experimental-nellore-cattle-population
#9
Bianca Ferreira Olivieri, Maria Eugênia Zerlotti Mercadante, Joslaine Noely Dos Santos Gonçalves Cyrillo, Renata Helena Branco, Sarah Figueiredo Martins Bonilha, Lucia Galvão de Albuquerque, Rafael Medeiros de Oliveira Silva, Fernando Baldi
The objective of this study was to identify genomic regions and metabolic pathways associated with dry matter intake, average daily gain, feed efficiency and residual feed intake in an experimental Nellore cattle population. The high-density SNP chip (Illumina High-Density Bovine BeadChip, 777k) was used to genotype the animals. The SNP markers effects and their variances were estimated using the single-step genome wide association method. The (co)variance components were estimated by Bayesian inference. The chromosome segments that are responsible for more than 1...
2016: PloS One
https://www.readbyqxmd.com/read/27696500/the-rs2274911-polymorphism-in-gprc6a-gene-is-associated-with-insulin-resistance-in-normal-weight-and-obese-subjects
#10
Andrea Di Nisio, Maria Santa Rocca, Gian Paolo Fadini, Luca De Toni, Giorgio Marcuzzo, Maria Cristina Marescotti, Marta Sanna, Mario Plebani, Roberto Vettor, Angelo Avogaro, Carlo Foresta
OBJECTIVE: Identification of the novel endocrine role of osteocalcin (OC) and its receptor GPRC6A has given rise to a new branch of research in OC/GPRC6A axis related to glucose metabolism. GPRC6A- and OC-deficient mice share features of the metabolic syndrome, in addition to male infertility. Recently, the polymorphism rs2274911 in GPRC6A was shown to be associated with testicular impairment. We aimed to investigate the role of rs2274911 polymorphism in glucose and lipid metabolism in a cohort of normal weight and obese subjects DESIGN, PATIENTS, SETTINGS: A total of 392 male and females, including 218 obese patients and 174 age-matched normal weight controls, were retrospectively selected...
October 1, 2016: Clinical Endocrinology
https://www.readbyqxmd.com/read/27689017/osteocalcin-is-necessary-and-sufficient-to-maintain-muscle-mass-in-older-mice
#11
Paula Mera, Kathrin Laue, Jianwen Wei, Julian Meyer Berger, Gerard Karsenty
OBJECTIVE: A decrease in muscle protein turnover and therefore in muscle mass is a hallmark of aging. Because the circulating levels of the bone-derived hormone osteocalcin decline steeply during aging in mice, monkeys and humans we asked here whether this hormone might regulate muscle mass as mice age. METHODS: We examined muscle mass and strength in mice lacking osteocalcin (Ocn-/-) or its receptor in all cells (Gprc6a-/-) or specifically in myofibers (Gprc6a Mck -/-) as well as in 9 month-old WT mice receiving exogenous osteocalcin for 28 days...
October 2016: Molecular Metabolism
https://www.readbyqxmd.com/read/27673554/osteocalcin-and-sex-hormone-binding-globulin-compete-on-a-specific-binding-site-of-gprc6a
#12
Luca De Toni, Diego Guidolin, Vincenzo De Filippis, Simone Tescari, Giacomo Strapazzon, Maria Santa Rocca, Alberto Ferlin, Mario Plebani, Carlo Foresta
The undercarboxylated form of osteocalcin (ucOC) regulates male fertility and energy metabolism, acting through the G protein-coupled receptor (GPRC)6A, thus forming a new pancreas-bone-testis axis. Recently, GPRC6A has also been suggested to mediate the nongenomic responses of free testosterone (T). However, these data did not consider the physiological scenario, where circulating T is mainly bound to sex hormone-binding globulin (SHBG) and only a small percentage circulates freely in the blood. Here, by the use of computational modelling, we document the existence of similar structural moieties between ucOC and SHBG that are predicted to bind to GPRC6A at docking analysis...
November 2016: Endocrinology
https://www.readbyqxmd.com/read/27338047/evidence-for-a-role-of-gprc6a-in-prostate-cancer-metastasis-based-on-case-control-and-in-vitro-analyses
#13
M Liu, Y-Y Zhao, F Yang, J-Y Wang, X-H Shi, X-Q Zhu, Y Xu, D Wei, L Sun, Y-G Zhang, K Yang, Y-C Qu, X Wang, S-Y Liang, X Chen, C-X Zhao, L Zhu, L Tang, C-G Zheng, Z Yang
OBJECTIVE: G protein-coupled receptor, family C, group 6, member A, (GPRC6A) is a prostate cancer (PCa) susceptibility gene and has been shown to regulate PCa progression. However, its role in PCa metastasis is largely unknown. The aim of this study was to confirm the association between GPRC6A and aggressive PCa in a case-control analysis, and to explore the function of GPRC6A in PCa metastasis in vitro. PATIENTS AND METHODS: The association of 14 single nucleotide polymorphisms (SNPs) of GPRC6A and linked to GPRC6A were evaluated with PCa risk and aggressive PCa in 916 subjects...
June 2016: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/27303307/the-calcium-sensing-receptor-and-integrins-in-cellular-differentiation-and-migration
#14
REVIEW
Sujeenthar Tharmalingam, David R Hampson
The calcium-sensing receptor (CaSR) is a widely expressed homodimeric G-protein coupled receptor structurally related to the metabotropic glutamate receptors and GPRC6A. In addition to its well characterized role in maintaining calcium homeostasis and regulating parathyroid hormone release, evidence has accumulated linking the CaSR with cellular differentiation and migration, brain development, stem cell engraftment, wound healing, and tumor growth and metastasis. Elevated expression of the CaSR in aggressive metastatic tumors has been suggested as a potential novel prognostic marker for predicting metastasis, especially to bone tissue where extracellular calcium concentrations may be sufficiently high to activate the receptor...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27291707/hindlimb-immobilization-but-not-castration-induces-reduction-of-undercarboxylated-osteocalcin-associated-with-muscle-atrophy-in-rats
#15
Xuzhu Lin, Erik Hanson, Andrew C Betik, Tara C Brennan-Speranza, Alan Hayes, Itamar Levinger
Undercarboxylated osteocalcin (ucOC) has been implicated in skeletal muscle insulin sensitivity and function. However, whether muscle mass and strength loss in atrophic conditions is related to a reduction in ucOC is not clear. We hypothesized that both immobilization and testosterone depletion would lead to reductions in ucOC, associated with not only the degree of muscle atrophy but also changes to atrophy signaling pathway(s) in male rats. We subjected 8-week-old male Fischer (F344) rats to 7 days of hindlimb immobilization 10 days after castration surgery...
June 13, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/27161228/extracellular-calcium-has-multiple-targets-to-control-cell-proliferation
#16
REVIEW
Thierry Capiod
Calcium channels and the two G-protein coupled receptors sensing extracellular calcium, calcium-sensing receptor (CaSR) and GPRC6a, are the two main means by which extracellular calcium can signal to cells and regulate many cellular processes including cell proliferation, migration and invasion of tumoral cells. Many intracellular signaling pathways are sensitive to cytosolic calcium rises and conversely intracellular signaling pathways can modulate calcium channel expression and activity. Calcium channels are undoubtedly involved in the former while the CaSR and GPRC6a are most likely to interfere with the latter...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27007074/evidence-for-osteocalcin-binding-and-activation-of-gprc6a-in-%C3%AE-cells
#17
Min Pi, Karan Kapoor, Ruisong Ye, Satoru Kenneth Nishimoto, Jeremy C Smith, Jerome Baudry, Leigh Darryl Quarles
The possibility that G protein-coupled receptor family C member A (GPRC6A) is the osteocalcin (Ocn)-sensing G protein-coupled receptor that directly regulates pancreatic β-cell functions is controversial. In the current study, we found that Ocn and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro. Computational models probe the structural basis of Ocn binding to GPRC6A and predict that the C-terminal hexapeptide docks to the extracellular side of the transmembrane domain of GPRC6A...
May 2016: Endocrinology
https://www.readbyqxmd.com/read/26994931/osteocalcin-improves-nonalcoholic-fatty-liver-disease-in-mice-through-activation-of-nrf2-and-inhibition-of-jnk
#18
Jing Du, Mingliang Zhang, Junxi Lu, Xueli Zhang, Qin Xiong, Yiting Xu, Yuqian Bao, Weiping Jia
Recent studies have demonstrated a protective effect of osteocalcin against nonalcoholic fatty liver disease (NAFLD), although the specific underlying mechanisms remain unclear. Nrf2 and JNK pathways play important roles in the pathogenesis of NAFLD. The present study aimed to investigate whether osteocalcin protects against NAFLD by regulating these pathways. Male C57/BL6J mice were fed a high-fat diet for 12 weeks to induce NAFLD and were treated with recombinant decarboxylate osteocalcin (30 ng/g) or vehicle by daily intraperitoneal injection during this period...
September 2016: Endocrine
https://www.readbyqxmd.com/read/26863991/l-arginine-promotes-gut-hormone-release-and-reduces-food-intake-in-rodents
#19
A Alamshah, A K McGavigan, E Spreckley, J S Kinsey-Jones, A Amin, I R Tough, H C O'Hara, A Moolla, K Banks, R France, G Hyberg, M Norton, W Cheong, A Lehmann, S R Bloom, H M Cox, K G Murphy
AIMS: To investigate the anorectic effect of L-arginine (L-Arg) in rodents. METHODS: We investigated the effects of L-Arg on food intake, and the role of the anorectic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), the G-protein-coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents. RESULTS: Oral gavage of L-Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet-induced obese mice...
May 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/26785252/murine-gprc6a-mediates-cellular-responses-to-l-amino-acids-but-not-osteocalcin-variants
#20
Patricia Rueda, Elizabeth Harley, Yao Lu, Gregory D Stewart, Stewart Fabb, Natalie Diepenhorst, Béatrice Cremers, Marie-Hélène Rouillon, Isabelle Wehrle, Anne Geant, Gwladys Lamarche, Katie Leach, William N Charman, Arthur Christopoulos, Roger J Summers, Patrick M Sexton, Christopher J Langmead
Phenotyping of Gprc6a KO mice has shown that this promiscuous class C G protein coupled receptor is variously involved in regulation of metabolism, inflammation and endocrine function. Such effects are described as mediated by extracellular calcium, L-amino acids, the bone-derived peptide osteocalcin (OCN) and the male hormone testosterone, introducing the concept of a bone-energy-metabolism-reproduction functional crosstalk mediated by GPRC6A. However, whilst the calcium and L-amino acid-sensing properties of GPRC6A are well established, verification of activity of osteocalcin at both human and mouse GPRC6A in vitro has proven somewhat elusive...
2016: PloS One
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