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Article ; Online: Robust GLP-1 secretion by basic L-amino acids does not require the GPRC6A receptor.

Clemmensen, Christoffer / Jørgensen, Christinna V / Smajilovic, Sanela / Bräuner-Osborne, Hans

2017 Volume 19, Issue 4, Page(s) 599–603

Abstract: 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 ... ...

Abstract	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. We found that oral administration of both L-arginine and L-ornithine significantly increased total plasma GLP-1 levels to a similar level in GPRC6A KO and WT mice 15 minutes after gavage (both amino acids) and accumulated up to 60 minutes after gavage (L-arginine). Conversely, GLP-1 secretion at the 30- and 60-minute time points in the KO mice was attenuated and did not reach statistical significance. In summary, these data confirm that L-arginine is a potent GLP-1 secretagogue and show that the main effect occurs independently of GPRC6A. In addition, this is the first study to show that also L-ornithine powerfully elicits GLP-1 release in vivo.
MeSH term(s)	Amino Acids, Basic/secretion ; Animals ; Arginine/administration & dosage ; Arginine/secretion ; Glucagon-Like Peptide 1/blood ; Glucagon-Like Peptide 1/secretion ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Ornithine/administration & dosage ; Ornithine/secretion ; Receptors, G-Protein-Coupled/physiology
Chemical Substances	Amino Acids, Basic ; GPRC6A protein, mouse ; Ligands ; Receptors, G-Protein-Coupled ; Glucagon-Like Peptide 1 (89750-14-1) ; Arginine (94ZLA3W45F) ; Ornithine (E524N2IXA3)
Language	English
Publishing date	2017-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.12845
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Article ; Online: Novel role of the calcium-sensing receptor in blood pressure modulation.

Smajilovic, Sanela / Tfelt-Hansen, Jacob

Hypertension (Dallas, Tex. : 1979)

2008 Volume 52, Issue 6, Page(s) 994–1000

MeSH term(s)	Animals ; Blood Pressure/physiology ; Humans ; Hypertension/physiopathology ; Receptors, Calcium-Sensing/physiology
Chemical Substances	Receptors, Calcium-Sensing
Language	English
Publishing date	2008-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.108.117689
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Zs.A 1488: Show issues

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Article ; Online: Promiscuous seven transmembrane receptors sensing L-α-amino acids.

Smajilovic, Sanela / Wellendorph, Petrine / Bräuner-Osborne, Hans

Current pharmaceutical design

2013 Volume 20, Issue 16, Page(s) 2693–2702

Abstract: A number of nutrient sensing seven trans-membrane (7TM) receptors have been identified and characterized over the past few years. While the sensing mechanisms to carbohydrates and free fatty acids are well understood, the molecular basis of amino acid ... ...

Abstract	A number of nutrient sensing seven trans-membrane (7TM) receptors have been identified and characterized over the past few years. While the sensing mechanisms to carbohydrates and free fatty acids are well understood, the molecular basis of amino acid sensing has recently come to the limelight. The present review describes the current status of promiscuous L-α-amino acid sensors, the calcium sensing receptor (CaSR), the GPRC6A receptor, the T1R1/T1R3 receptor and also their molecular pharmacology, expression pattern and physiological significance.
MeSH term(s)	Amino Acids/chemistry ; Amino Acids/metabolism ; Animals ; Humans ; Protein Structure, Secondary ; Receptors, Calcium-Sensing/chemistry ; Receptors, Calcium-Sensing/metabolism ; Receptors, Cytoplasmic and Nuclear/chemistry ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Amino Acids ; Receptors, Calcium-Sensing ; Receptors, Cytoplasmic and Nuclear ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2013-07-09
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1304236-1
ISSN	1873-4286 ; 1381-6128
ISSN (online)	1873-4286
ISSN	1381-6128
DOI	10.2174/13816128113199990576
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Zs.A 4714: Show issues

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Article: Calcium acts as a first messenger through the calcium-sensing receptor in the cardiovascular system.

Smajilovic, Sanela / Tfelt-Hansen, Jacob

Cardiovascular research

2007 Volume 75, Issue 3, Page(s) 457–467

Abstract: It is well known that calcium is an important second messenger in the cardiovascular system. However, recent studies suggest that, in addition to its many functions as an intracellular messenger, Ca(2+) may also be an extracellular first messenger ... ...

Abstract	It is well known that calcium is an important second messenger in the cardiovascular system. However, recent studies suggest that, in addition to its many functions as an intracellular messenger, Ca(2+) may also be an extracellular first messenger through the calcium-sensing receptor (CaR). The CaR belongs to family C of the G-protein-coupled receptors, which are also known as seven transmembrane domain receptors. The CaR receptor is expressed in all major organs involved in Ca(2+) homeostasis. Furthermore, increasing evidence suggests that the CaR is also involved in regulating various cellular functions in tissues not involved in Ca(2+) homeostasis. Recently, expression of a functional CaR has also been reported in crucial components of the cardiovascular system. It has previously been shown that the CaR is functionally expressed in the atria and ventricle of the rat heart. In blood vessels, the CaR protein was first reported in perivascular nerves of rat mesenteric resistance arteries, and was proposed to modulate myogenic tone in the arteries. Since then, the CaR has been detected in homogenates of whole vessels from rat subcutaneous small arteries and in endothelial cells from rat mesenteric and porcine coronary arteries. Furthermore, a recent report demonstrated that the CaR is present in endothelial cells from human aorta and that it stimulates production of nitric oxide in these cells. Taken together, these results indicate that the CaR present in blood vessels may have a physiological role in modulation of arterial blood pressure. This review discusses CaR expression and function, with a focus on the role of the CaR in the cardiovascular system.
MeSH term(s)	Animals ; Calcium/physiology ; Calcium Signaling/physiology ; Cardiovascular System/metabolism ; Extracellular Space/metabolism ; Heart Diseases/metabolism ; Humans ; Receptors, Calcium-Sensing/metabolism
Chemical Substances	Receptors, Calcium-Sensing ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2007-08-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1016/j.cardiores.2007.03.015
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Zs.A 565: Show issues

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Article ; Online: The calcium-sensing receptor and calcimimetics in blood pressure modulation.

Smajilovic, Sanela / Yano, Shozo / Jabbari, Reza / Tfelt-Hansen, Jacob

British journal of pharmacology

2011 Volume 164, Issue 3, Page(s) 884–893

Abstract: Calcium is a crucial second messenger in the cardiovascular system. However, calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular concentration (Ca(2+)(o)), the calcium-sensing receptor (CaR). ...

Abstract	Calcium is a crucial second messenger in the cardiovascular system. However, calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular concentration (Ca(2+)(o)), the calcium-sensing receptor (CaR). The most prominent physiological function of the CaR is to maintain the extracellular Ca(2+) level in a very tight range by regulating the circulating levels of parathyroid hormone (PTH). This control over PTH and Ca(2+) levels is partially lost in patients suffering from primary and secondary hyperparathyroidism. Allosteric modulators of the CaR (calcimimetics) are the first drugs in their class to become available for clinical use and have been shown to successfully treat certain forms of primary and secondary hyperparathyroidism. In addition, several studies suggest beneficial effects of calcimimetics on cardiovascular risk factors associated with hyperparathyroidism. Although a plethora of studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. However, several studies point toward a possibility that the CaR might be involved in the regulation of vascular tone. This review will summarize the current knowledge on the possible functions of the CaR and calcimimetics on blood pressure regulation.
MeSH term(s)	Animals ; Blood Pressure/drug effects ; Calcimimetic Agents/pharmacology ; Calcimimetic Agents/therapeutic use ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/metabolism ; Humans ; Receptors, Calcium-Sensing/metabolism
Chemical Substances	Calcimimetic Agents ; Receptors, Calcium-Sensing
Language	English
Publishing date	2011-03-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/j.1476-5381.2011.01317.x
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Article ; Online: Effect of intermittent versus continuous parathyroid hormone in the cardiovascular system of rats.

Smajilovic, Sanela / Schaal-Jensen, Rasmus / Jabbari, Reza / Smajilovic, Una / Haunso, Stig / Tfelt-Hansen, Jacob

The open cardiovascular medicine journal

2010 Volume 4, Page(s) 110–116

Abstract: Objective: PTH increases ionic calcium concentration in the serum, acting primarily on bone and kidney cells through the type 1 PTH receptor. Interestingly, PTH stimulates bone formation when administrated intermittently but causes severe bone loss with ...

Abstract	Objective: PTH increases ionic calcium concentration in the serum, acting primarily on bone and kidney cells through the type 1 PTH receptor. Interestingly, PTH stimulates bone formation when administrated intermittently but causes severe bone loss with continuous administration. Daily injections of PTH are used as the most promising anabolic agent in the treatment of severe osteoporosis. Elevated PTH is reported an independent risk factor for left ventricle hypertrophy. Design: in rats we investigated the effect of intermittent and continuous administration of PTH on blood pressure, heart rate and development of cardiac hypertrophy and fibrosis. Results: We did not find PTH to induce heart hypertrophy. In contrast, continuous administration of PTH the mRNA level of a hypertrophic marker gene, atrial natriuretic peptide. When comparing the effect of continuously versus injected PTH collagen 1 mRNA was significantly higher in continuously treated animals. Conclusion: our data demonstrated a decrease in heart rate upon continuous administration of PTH in rats. No changes in blood pressure were observed. Moreover, neither intermittent nor continuous administration of PTH induced ventricular hypertrophy. But continuous PTH induced a marker of collagen 1. Thus, these data did not reveal any negative effects of the injection of PTH on the cardiovascular system.
Language	English
Publishing date	2010-03-31
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2396047-4
ISSN	1874-1924 ; 1874-1924
ISSN (online)	1874-1924
ISSN	1874-1924
DOI	10.2174/1874192401004010110
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Article ; Online: Increased susceptibility to diet-induced obesity in GPRC6A receptor knockout mice.

Clemmensen, Christoffer / Smajilovic, Sanela / Madsen, Andreas N / Klein, Anders B / Holst, Birgitte / Bräuner-Osborne, Hans

The Journal of endocrinology

2013 Volume 217, Issue 2, Page(s) 151–160

Abstract: The recently identified G protein-coupled receptor GPRC6A is activated by dietary amino acids and expressed in multiple tissues. Although the receptor is hypothesised to exert biological impact on metabolic and endocrine-related parameters, the role of ... ...

Abstract	The recently identified G protein-coupled receptor GPRC6A is activated by dietary amino acids and expressed in multiple tissues. Although the receptor is hypothesised to exert biological impact on metabolic and endocrine-related parameters, the role of the receptor in obesity and metabolic complications is still elusive. In the present study, we investigated the impact of GPRC6A deficiency in a murine model of diet-induced obesity (DIO). Male Gprc6a knockout (KO) mice and WT littermates were subjected to a high-fat diet (HFD) for 25 weeks and exposed to comprehensive metabolic phenotyping. A significant increase in body weight, corresponding to a selective increase in body fat, was observed in Gprc6a KO mice exposed to an HFD relative to WT controls. The obese phenotype was linked to subtle perturbations in energy homoeostasis as GPRC6A deficiency resulted in chronic hyperphagia and decreased locomotor activity. Moreover, diet-induced obese Gprc6a KO mice had increased circulating insulin and leptin levels relative to WT animals, thereby demonstrating that endocrine abnormalities associate with the reported disturbances in energy balance. The phenotype was further accompanied by disruptions in glucose metabolism showing that Gprc6a KO mice on an HFD display increased susceptibility to develop metabolic-related disorders. Altogether, these data suggest that the amino acid sensing receptor GPRC6A plays an important role in resistance to DIO and metabolic complications. Future studies will illuminate the underlying molecular mechanisms mediating the herein reported findings and potentially facilitate the development of novel therapeutic compounds targeting the GPRC6A receptor.
MeSH term(s)	Animals ; Body Composition/physiology ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Eating/physiology ; Energy Metabolism/physiology ; Genetic Predisposition to Disease/genetics ; Glucose/metabolism ; Insulin/blood ; Leptin/blood ; Male ; Mice ; Mice, Knockout ; Obesity/etiology ; Obesity/genetics ; Obesity/metabolism ; Phenotype ; Receptors, G-Protein-Coupled/deficiency ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	GPRC6A protein, mouse ; Insulin ; Leptin ; Receptors, G-Protein-Coupled ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2013-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3028-4
ISSN	1479-6805 ; 0022-0795
ISSN (online)	1479-6805
ISSN	0022-0795
DOI	10.1530/JOE-12-0550
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Article ; Online: Novel strategies in drug discovery of the calcium-sensing receptor based on biased signaling.

Thomsen, Alex Rojas Bie / Smajilovic, Sanela / Bräuner-Osborne, Hans

Current drug targets

2007 Volume 13, Issue 10, Page(s) 1324–1335

Abstract: A hallmark of chronic kidney disease is hyperphosphatemia due to renal phosphate retention. Prolonged parathyroid gland exposure to hyperphosphatemia leads to secondary hyperparathyroidism characterized by hyperplasia of the glands and excessive ... ...

Abstract	A hallmark of chronic kidney disease is hyperphosphatemia due to renal phosphate retention. Prolonged parathyroid gland exposure to hyperphosphatemia leads to secondary hyperparathyroidism characterized by hyperplasia of the glands and excessive secretion of parathyroid hormone (PTH), which causes renal osteodystrophy. PTH secretion from the parathyroid glands is controlled by the calcium-sensing receptor (CaSR) that senses extracellular calcium. High extracellular calcium activates the CaSR causing inhibition of PTH secretion through multiple signaling pathways. Cinacalcet is the first drug targeting the CaSR and can be used to effectively control and reduce PTH secretion in PTH-related diseases. Cinacalcet is a positive allosteric modulator of the CaSR and affects PTH secretion from parathyroid glands by shifting the calcium-PTH concentration-response curve to the left. One major disadvantage of cinacalcet is its hypocalcemic side effect, which may be caused by increased CaSR-mediated calcitonin secretion from the thyroid gland. However, multiple studies indicate that PTH and calcitonin secretion are stimulated by different signaling pathways, and therefore it might be possible to develop a CaSR activating drug that selectively activates signaling pathways that inhibit PTH secretion while having no effect on signaling pathways involved in calcitonin secretion. Such a drug would have the same therapeutic value as cinacalcet in lowering PTH secretion while eliminating the side effect of hypocalcemia by virtue of it not affecting calcitonin secretion. The present review will focus on recent advancements in understanding signaling and biased signaling of the CaSR, and how that may be utilized to discover new and smarter drugs targeting the CaSR.
MeSH term(s)	Calcium/metabolism ; Drug Discovery ; Humans ; Parathyroid Hormone/metabolism ; Receptors, Calcium-Sensing/drug effects ; Receptors, Calcium-Sensing/metabolism ; Receptors, Calcium-Sensing/physiology ; Signal Transduction
Chemical Substances	Parathyroid Hormone ; Receptors, Calcium-Sensing ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2007-06-30
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2064859-5
ISSN	1873-5592 ; 1389-4501
ISSN (online)	1873-5592
ISSN	1389-4501
DOI	10.2174/138945012802429642
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Zs.A 5578: Show issues

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Article ; Online: L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances.

Clemmensen, Christoffer / Madsen, Andreas N / Smajilovic, Sanela / Holst, Birgitte / Bräuner-Osborne, Hans

Amino acids

2012 Volume 43, Issue 3, Page(s) 1265–1275

Abstract: L-Arginine (L-Arg) is a conditionally essential amino acid and a natural constituent of dietary proteins. Studies in obese rats and type 2 diabetic humans have indicated that dietary supplementation with L-Arg can diminish gain in white adipose tissue ( ... ...

Abstract	L-Arginine (L-Arg) is a conditionally essential amino acid and a natural constituent of dietary proteins. Studies in obese rats and type 2 diabetic humans have indicated that dietary supplementation with L-Arg can diminish gain in white adipose tissue (WAT) and improve insulin sensitivity. However, the effects of L-Arg on glucose homeostasis, body composition and energy metabolism remain unclear. In addition, no studies have, to our knowledge, examined whether L-Arg has beneficial effects as a dietary supplement in the mouse model. In the present study, we investigated the effects of L-Arg supplementation to male C57BL/6 mice on an array of physiological parameters. L-Arg supplemented mice were maintained on a low-protein diet and body composition, appetite regulation, glucose tolerance, insulin sensitivity and energy expenditure were evaluated. A significant reduction in epididymal WAT was observed in L-Arg supplemented mice compared with mice fed an isocaloric control diet. Surprisingly, the L-Arg supplemented animals were hyperphagic corresponding to a highly significant decrease in feed efficiency, as body weight developed in a similar pattern in both experimental groups. Glucose homeostasis experiments revealed a major effect of L-Arg supplementation on glucose tolerance and insulin sensitivity, interestingly, independent of a parallel regulation in whole-body adiposity. Increased L-Arg ingestion also raised energy expenditure; however, no concurrent effect on locomotor activity, substrate metabolism or expression of uncoupling proteins (UCP1 and UCP2) in adipose tissues was displayed. In conclusion, dietary L-Arg supplementation substantially affects an array of metabolic-associated parameters including a reduction in WAT, hyperphagia, improved insulin sensitivity and increased energy expenditure in mice fed a low-protein diet.
MeSH term(s)	Adipose Tissue, White/drug effects ; Adipose Tissue, White/pathology ; Adiposity/drug effects ; Animals ; Arginine/administration & dosage ; Arginine/adverse effects ; Blood Glucose ; Diet, Protein-Restricted/adverse effects ; Dietary Supplements ; Energy Intake/drug effects ; Energy Metabolism/drug effects ; Gene Expression/drug effects ; Genes, Mitochondrial ; Glucose/metabolism ; Homeostasis ; Hyperphagia/chemically induced ; Hypoglycemic Agents/administration & dosage ; Hypoglycemic Agents/adverse effects ; Insulin/blood ; Insulin Resistance ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Motor Activity/drug effects ; Oxygen Consumption/drug effects
Chemical Substances	Blood Glucose ; Hypoglycemic Agents ; Insulin ; Arginine (94ZLA3W45F) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2012-09
Publishing country	Austria
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1121341-3
ISSN	1438-2199 ; 0939-4451
ISSN (online)	1438-2199
ISSN	0939-4451
DOI	10.1007/s00726-011-1199-1
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Zs.A 3490: Show issues

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Article ; Online: The L-α-amino acid receptor GPRC6A is expressed in the islets of Langerhans but is not involved in L-arginine-induced insulin release.

Smajilovic, Sanela / Clemmensen, Christoffer / Johansen, Lars Dan / Wellendorph, Petrine / Holst, Jens Juul / Thams, Peter Grevsen / Ogo, Egbuna / Bräuner-Osborne, Hans

Amino acids

2012 Volume 44, Issue 2, Page(s) 383–390

Abstract: GPRC6A is a seven-transmembrane receptor activated by a wide range of L-α-amino acids, most potently by L-arginine and other basic amino acids. The receptor is broadly expressed, but its exact physiological role remains to be elucidated. It is well ... ...

Abstract	GPRC6A is a seven-transmembrane receptor activated by a wide range of L-α-amino acids, most potently by L-arginine and other basic amino acids. The receptor is broadly expressed, but its exact physiological role remains to be elucidated. It is well established that L-arginine stimulates insulin secretion; therefore, the receptor has been hypothesized to have a role in regulating glucose metabolism. In this study, we demonstrate that GPRC6A is expressed in islets of Langerhans, but activation of the receptor by L-arginine did not stimulate insulin secretion. We also investigated central metabolic parameters in GPRC6A knockout mice compared with wildtype littermates and found no difference in glucose metabolism or body fat percentage when mice were administered a standard chow diet. In conclusion, our data do not support a role for GPRC6A in L-arginine-induced insulin release and glucose metabolism under normal physiological conditions.
MeSH term(s)	Animals ; Arginine/metabolism ; Glucose/metabolism ; Insulin/metabolism ; Insulin Secretion ; Islets of Langerhans/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	GPRC6A protein, mouse ; Insulin ; Receptors, G-Protein-Coupled ; Arginine (94ZLA3W45F) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2012-06-20
Publishing country	Austria
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1121341-3
ISSN	1438-2199 ; 0939-4451
ISSN (online)	1438-2199
ISSN	0939-4451
DOI	10.1007/s00726-012-1341-8
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