Sensing Extracellular Calcium – An Insight into the Structure and Function of the Calcium-Sensing Receptor (CaSR)

Chavez-Abiega, Sergei; Mos, Iris; Centeno, Patricia P.; Elajnaf, Taha; Schlattl, Wolfgang; Ward, Donald T.; Goedhart, Joachim; Kállay, Enikö

doi:10.1007/978-3-030-12457-1_41

Cited by 49 publications

(39 citation statements)

References 163 publications

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“…ERK1/2 activation was involved in CaSR-induced autophagy induction by spermine and not by cinacalcet in preadipocytes. This may reflect the well-described biased agonism of CaSR activation [ 11 , 12 , 46 ], which has been documented for polyamines toward ERK1/2 signaling in HEK293-CaSR cells [ 46 ]. Our previous reports showed that CaSR activation by cinacalcet triggers ERK1/2 pathway to regulate preadipocyte proliferation [ 13 ] and inflammasome activation [ 14 ]; however, this pathway probably does not mediate the effect on autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…CaSR was originally described for its key role in parathyroid hormone secretion and circulating calcium homeostasis, and subsequent research has shown its relevance in inflammation-related disorders [ 9 , 10 ], among others. CaSR can be activated by several ligands, including cations, antibiotics, polyamines and pharmacological compounds [ 11 ]. Multiple intracellular pathways can be triggered depending on the receptor’s conformational state induced by a given CaSR ligand, a phenomenon called biased agonism [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…CaSR can be activated by several ligands, including cations, antibiotics, polyamines and pharmacological compounds [ 11 ]. Multiple intracellular pathways can be triggered depending on the receptor’s conformational state induced by a given CaSR ligand, a phenomenon called biased agonism [ 11 , 12 ]. In preadipocytes, the allosteric CaSR activator cinacalcet induces ERK1/2 activation, resulting in cell proliferation and NLRP3 induction [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Calcium-Sensing Receptor in Adipose Tissue: Possible Association with Obesity-Related Elevated Autophagy

Mattar

Sanhueza

Yuri

et al. 2020

IJMS

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Autophagy is upregulated in adipose tissue (AT) from people with obesity. We showed that activation of the calcium-sensing receptor (CaSR) elevates proinflammatory cytokines through autophagy in preadipocytes. Our aim is to understand the role of CaSR on autophagy in AT from humans with obesity. We determined mRNA and protein levels of CaSR and markers of autophagy by qPCR and western blot in human visceral AT explants or isolated primary preadipocytes (60 donors: 72% female, 23–56% body fat). We also investigated their association with donors’ anthropometric variables. Donors’ % body fat and CaSR mRNA expression in AT were correlated (r = 0.44, p < 0.01). CaSR expression was associated with mRNA levels of the autophagy markers atg5 (r = 0.37, p < 0.01), atg7 (r = 0.29, p < 0.05) and lc3b (r = 0.40, p < 0.01). CaSR activation increased becn and atg7 mRNA expression in AT. CaSR activation also upregulated LC3II by ~50%, an effect abolished by the CaSR inhibitor. Spermine (CaSR agonist) regulates LC3II through the ERK1/2 pathway. Structural equation model analysis suggests a link between donors’ AT CaSR expression, AT autophagy and expression of Tumor Necrosis Factor alpha TNF-α. CaSR expression in visceral AT is directly associated with % body fat, and CaSR activation may contribute to obesity-related disruption in AT autophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Calcium-Sensing Receptor in Adipose Tissue: Possible Association with Obesity-Related Elevated Autophagy

Mattar

Sanhueza

Yuri

et al. 2020

IJMS

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“…1 The serum calcium concentration is tightly regulated by the calcium sensing receptor present on parathyroid gland which is exquisitely sensitive to changes in calcium concentrations and responds by secreting PTH to reductions in calcium concentration. 6 The net effect of PTH is calcium efflux from bone, reabsorption from kidney, and absorption from the gastrointestinal tract. In the setting of hypercalcemia, PTH is suppressed resulting in calcium influx into bone, and decreased gastrointestinal absorption and kidney reabsorption.…”

Section: Discussionmentioning

confidence: 99%

When CKD-MBD is not just CKD-MBD, a case of humoral hypercalcemia of malignancy in a dialysis patient

Gandhi

Shah

2020

Journal of Onco-Nephrology

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Patients on maintenance hemodialysis have dysregulations of calcium and phosphorus homeostasis which results in a plethora of mineral and bone pathologies. Management is typically focused on maintenance eucalcemia and limiting hyperphosphatemia while avoiding extremes of intact parathyroid hormone. Hypercalcemia in this setting is often iatrogenic. We present a case of humoral hypercalcemia of malignancy initially thought to be iatrogenic due to mineral bone management and discuss the overlap of management of hypercalcemia and management of mineral bone disease in end stage kidney disease. We highlight the relationship between malignancy and end stage kidney disease and the increased risk of hypercalcemia associated with malignancy.

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“…Because of its pathophysiological importance, various synthetic PAMs and NAMs of CaSR have been identified and are in clinical use. The allosteric modulation of CaSR by synthetic drugs has been recently reviewed (Hannan et al, 2016;Chavez-Abiega et al, 2020;Leach et al, 2020). Since the 1990's the term calcimimetics and calcilytics, have been used for drugs that mimic or antagonize the effect of extracellular Ca 2+ on CaSR activity, respectively.…”

Section: Synthetic Drugs As Allosteric Ligands Of Calcium-sensing Recmentioning

confidence: 99%

G Protein-Coupled Receptors in Taste Physiology and Pharmacology

2020

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Heterotrimeric G protein-coupled receptors (GPCRs) comprise the largest receptor family in mammals and are responsible for the regulation of most physiological functions. Besides mediating the sensory modalities of olfaction and vision, GPCRs also transduce signals for three basic taste qualities of sweet, umami (savory taste), and bitter, as well as the flavor sensation kokumi. Taste GPCRs reside in specialised taste receptor cells (TRCs) within taste buds. Type I taste GPCRs (TAS1R) form heterodimeric complexes that function as sweet (TAS1R2/TAS1R3) or umami (TAS1R1/TAS1R3) taste receptors, whereas Type II are monomeric bitter taste receptors or kokumi/calcium-sensing receptors. Sweet, umami and kokumi receptors share structural similarities in containing multiple agonist binding sites with pronounced selectivity while most bitter receptors contain a single binding site that is broadly tuned to a diverse array of bitter ligands in a non-selective manner. Tastant binding to the receptor activates downstream secondary messenger pathways leading to depolarization and increased intracellular calcium in TRCs, that in turn innervate the gustatory cortex in the brain. Despite recent advances in our understanding of the relationship between agonist binding and the conformational changes required for receptor activation, several major challenges and questions remain in taste GPCR biology that are discussed in the present review. In recent years, intensive integrative approaches combining heterologous expression, mutagenesis and homology modeling have together provided insight regarding agonist binding site locations and molecular mechanisms of orthosteric and allosteric modulation. In addition, studies based on transgenic mice, utilizing either global or conditional knock out strategies have provided insights to taste receptor signal transduction mechanisms and their roles in physiology. However, the need for more functional studies in a physiological context is apparent and would be enhanced by a crystallized structure of taste receptors for a more complete picture of their pharmacological mechanisms.

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Sensing Extracellular Calcium – An Insight into the Structure and Function of the Calcium-Sensing Receptor (CaSR)

Cited by 49 publications

References 163 publications

Calcium-Sensing Receptor in Adipose Tissue: Possible Association with Obesity-Related Elevated Autophagy

Calcium-Sensing Receptor in Adipose Tissue: Possible Association with Obesity-Related Elevated Autophagy

When CKD-MBD is not just CKD-MBD, a case of humoral hypercalcemia of malignancy in a dialysis patient

G Protein-Coupled Receptors in Taste Physiology and Pharmacology

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