Positive Allosteric Modulation of the Calcium-sensing Receptor by Physiological Concentrations of Glucose

Medina, Johan; Nakagawa, Yuko; Nagasawa, Mitsuru; Fernandez, Anny; Sakaguchi, Kazushige; Kitaguchi, Tetsuya; Kojima, Itaru

doi:10.1074/jbc.m116.729863

Cited by 25 publications

(29 citation statements)

References 31 publications

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“…Second, it has been recently demonstrated that glucose and other sugars act as type II calcimimetics, enhancing CaSR affinity for Ca 2+ . 71 This could be relevant in the apical membrane of the DCT because all of the filtered glucose is reabsorbed in the proximal tubule and therefore these cells are not continuously exposed to glucose. In patients with diabetes, the excess filtered glucose often escapes reabsorption in the proximal tubule, allowing a significant amount of glucose in the tubular fluid that reaches the DCT.…”

Section: Discussionmentioning

confidence: 99%

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Bazúa‐Valenti

Rojas‐Vega

Castañeda‐Bueno

et al. 2018

JASN

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Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle's loop controls Ca excretion and NaCl reabsorption in response to extracellular Ca However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. We used a combination of and models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Thiazide-sensitive Na uptake assays in oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Activation of CaSR can increase NCC activity the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca reabsorption, further promoting hypercalciuria.

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Section: Discussionmentioning

confidence: 99%

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Bazúa‐Valenti

Rojas‐Vega

Castañeda‐Bueno

et al. 2018

JASN

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“…Extracellular Ca 2+ -sensing receptor (CaSR) — a G protein-coupled receptor that was originally identified in the parathyroid glands and is a key player in the body’s Ca 2+ homeostasis — is expressed in subsets of taste bud cells and is a possible transducer for kokumi stimuli 239 . CaSR is reported to be allosterically modulated by sucrose and several other natural and synthetic sweeteners 240 , and this modulation may account for the interaction between kokumi compounds and other taste stimuli.…”

Section: Figurementioning

confidence: 99%

Taste buds: cells, signals and synapses

Roper¹,

2017

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The past decade has witnessed a consolidation and refinement of the extraordinary progress made in taste research. This Review describes recent advances in our understanding of taste receptors, taste buds, and the connections between taste buds and sensory afferent fibres. The article discusses new findings regarding the cellular mechanisms for detecting tastes, new data on the transmitters involved in taste processing and new studies that address longstanding arguments about taste coding.

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“…It should be noted that the pattern of changes in [Ca 2+ ] c was quite similar to that observed in glucose‐stimulated HEK‐T1R3 cells and 3OMG‐stimulated MIN6 cells. To our surprise, CaSR was very sensitive to glucose, and we observed a [Ca 2+ ] c response when ambient glucose concentration was raised from 3 to 4 mM . The maximal effect of glucose was obtained at 5 mM.…”

Section: Cell‐surface Receptor Activated By Glucosementioning

confidence: 67%

“…To address this possibility, we first examined whether or not CaSR can be activated by glucose to some extent. We established a stable HEK293 cell line expressing CaSR (HEK‐CaSR cells) . In these cells, a homodimer of CaSR was formed.…”

Section: Cell‐surface Receptor Activated By Glucosementioning

confidence: 99%

“…This compound inhibits the action of artificial sweeteners on [Ca 2+ ] c nearly completely, while elevation of [Ca 2+ ] c induced by high concentration of KCl was not affected . The effect of lactisole is rather specific to T1R3 and it does not affect other class C GPCR including T1R1, T1R2 and CaSR . Using this compound, we addressed the role of the glucose‐sensing receptor in the action of glucose on [Ca 2+ ] c .…”

Section: Role Of the Glucose‐sensing Receptor In Pancreatic β‐Cellsmentioning

confidence: 99%

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Role of the glucose‐sensing receptor in insulin secretion

Kojima

Medina

Nakagawa

2017

Diabetes Obesity Metabolism

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Glucose is a primary stimulator of insulin secretion. It has been thought that glucose exerts its effect by a mechanism solely dependent on glucose metabolism. We show here that glucose induces rapid Ca 2+ and cyclic AMP signals in β-cells. These rapid signals are independent of glucose-metabolism and are reproduced by non-metabolizable glucose analogues. These results led us to postulate that glucose activates a cell-surface receptor, namely the glucose-sensing receptor. Rapid signals induced by glucose are blocked by inhibition of a sweet taste receptor subunit T1R3 and a calcium-sensing receptor subunit CaSR. In accordance with these observations, T1R3 and CaSR form a heterodimer. In addition, a heterodimer of T1R3 and CaSR is activated by glucose. These results suggest that a heterodimer of T1R3 and CaSR is a major component of the glucose-sensing receptor. When the glucose-sensing receptor is blocked, glucose-induced insulin secretion is inhibited. Also, ATP production is significantly attenuated by the inhibition of the receptor. Conversely, stimulation of the glucose-sensing receptor by either artificial sweeteners or non-metabolizable glucose analogue increases ATP. Hence, the glucose-sensing receptor signals promote glucose metabolism. Collectively, glucose activates the cell-surface glucose-sensing receptor and promotes its own metabolism. Glucose then enters the cells and is metabolized through already activated metabolic pathways. The glucosesensing receptor is a key molecule regulating the action of glucose in β-cells.glucose, glucose-sensing receptor, sweet taste receptorGlucose is a primary fuel in the body, and in some organs, for example, in neurons in the central nervous system, glucose is the only fuel utilized in the cells. Accordingly, the plasma concentration of glucose is regulated tightly by the actions of various glucose-regulating hormones and the autonomic nervous system. Among these glucoseregulating hormones, insulin is a principal hormone regulating glucose metabolism in the body. 1 Insulin not only regulates the plasma concentration of glucose but it also modulates metabolism of glucose in many organs including the liver, skeletal muscle and adipose tissue.This important hormone, insulin, is produced and secreted solely in pancreatic β-cells. In these cells, various types of fuels, hormones and neurotransmitters regulate insulin secretion. Among them, the most important regulator of insulin secretion is glucose. Thus, glucose is a primary stimulator of insulin secretion and, unlike other modulators of secretion, it is able to stimulate insulin secretion by itself. 1The action of glucose in pancreatic β-cells has been investigated for several decades, and in particular, the mechanism by which glucose stimulates insulin secretion has been a matter of extensive research. According to the current understanding, glucose stimulates insulin secretion by a mechanism totally dependent on glucose metabolism. 2,3 Thus, glucose enters β-cell and is metabolized through the glycolytic pathway a...

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Positive Allosteric Modulation of the Calcium-sensing Receptor by Physiological Concentrations of Glucose

Cited by 25 publications

References 31 publications

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Taste buds: cells, signals and synapses

Role of the glucose‐sensing receptor in insulin secretion

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