Expression of an extracellular calcium-sensing receptor in rat stomach

Cheng, Ivan; Qureshi, Imtiaz; Chattopadhyay, Naibedya; Qureshi, Athar M.; Butters, Robert R.; Hall, Amy E.; Cima, Robert R.; Rogers, Kimberly V.; Hebert, Steven C.; Geibel, John P.; Brown, Edward M.; Soybel, David I.

doi:10.1016/s0016-5085(99)70235-0

Cited by 114 publications

(83 citation statements)

References 23 publications

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“…For acid-secreting organs such as the stomach and the kidney, the CaR will probably experience the alkaline tide associated with acid secretion from the apical membrane. In the stomach, the CaR is expressed in G (gastrinsecreting) cells as well as the acid-secreting gastric parietal cells, in which activation of the CaR seems to be associated with acid secretion (27)(28)(29). The alkalinization of the interstitial fluid adjacent to the basolateral membrane could lead to facilitation of acid secretion under conditions in which local Ca 2ϩ may remain largely unchanged.…”

Section: Discussionmentioning

confidence: 99%

pH Sensing by the Calcium-sensing Receptor

Quinn

Bai

Brown

2004

Journal of Biological Chemistry

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129

107

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The calcium-sensing receptor (CaR) is activated by small changes in the ionic extracellular calcium concentration (Ca o ) within the physiological range, allowing the parathyroid gland to regulate serum Ca o ; however, the CaR is also distributed in a number of other tissues where it may sense other endogenous agonists and modulators. CaR agonists are polycationic molecules, and our previous studies suggest that charged residues in the extracellular domain of the CaR are critical for receptor activation through electrostatic interactions. Therefore, pH could also potentially modulate CaR activation by its polycationic agonists. Changes in the concentration of extracellular H ؉ substantially altered the activation of the CaR by Ca o and other CaR agonists. The effects of external pH on the CaR's sensitivity to its agonists were observed for both acidic and basic deviations from physiological pH of 7.4, with increases in pH rendering the receptor more sensitive to activation by Ca o and decreases in pH producing the converse effect. At pH values more acidic than 5.5, CaR sensitivity to its agonists showed some recovery. Changes in the intracellular pH could not account for the effects of external pH on CaR sensitivity to its agonists. Other G-proteincoupled receptors, which are endogenously expressed in human embryonic kidney 293 cells, showed little change in activity with alterations in external pH or effects opposite those found for the CaR. Extracellular pH directly alters the CaR in the case of Ca o and Mg o activation; however, the charges on many organic and inorganic agonists are pH-dependent. Activating CaR mutations show reduced pH o modulation, suggesting a molecular mechanism for increased CaR activity at physiological pH o . Several CaR-expressing tissues, including regions of the stomach, the kidney, bone, and the brain, could potentially use the CaR as a sensor for pH and acid-base status.

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Section: Discussionmentioning

confidence: 99%

pH Sensing by the Calcium-sensing Receptor

Quinn

Bai

Brown

2004

Journal of Biological Chemistry

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129

107

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“…The CaR is widespread in the brain and develops early in ontogeny (Chattopadhyay et al, 1997). The distribution of mRNA encoding the CaR in the brain (Rogers et al, 1997) and the gut (Cheng et al, 1999) is quite extensive. Stimulation of the brain CaR expressed in a transfected cell line activates phospholipase C and causes accumulation of IP 3 (Ruat et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Ca²⁺-Evoked Serotonin Secretion by Parafollicular Cells: Roles in Signal Transduction of Phosphatidylinositol 3′-kinase, and the γ and ζ Isoforms of Protein Kinase C

et al. 2000

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Parafollicular (PF) cells secrete 5-HT in response to stimulation of a G-protein-coupled Ca 2ϩ receptor (CaR) by increased extracellular Ca 2ϩ (1[Ca 2ϩ ] e ). We tested the hypothesis that protein kinase C (PKC) participates in stimulus-secretion coupling. Immunoblots from membrane and cytosolic fractions of isolated PF cells revealed conventional (␣, ␤I, and ␥), novel (␦ and ⑀), and atypical ( / and ) PKCs. Only PKC␥ was found to have been translocated to the membrane fraction when secretion of 5-HT was evoked by 1[Ca 2ϩ ] e or phorbol esters. Although phorbol downregulation caused PKC␥ to disappear, secretion was only partially inhibited. A similar reduction of 1[Ca 2ϩ ] e -evoked secretion was produced by inhibitors of conventional and/or novel PKCs (Gö 6976, calphostin C, and pseudoA), and these compounds did not inhibit secretion at all when applied to phorbol-downregulated cells. In contrast, the phorbol downregulation-resistant component of secretion was abolished by pseudoZ, which inhibits the atypical PKC . Stimulation of PF cells with 1[Ca 2ϩ ] e increased the activity of immunoprecipitated PKC (but not PKC / ), and the activity of this PKC was inhibited by pseudoZ. PF cells were found to express regulatory (p85) and catalytic (p110␣ and p110␤) subunits of phosphatidylinositol 3Ј-kinase (PI3Ј-kinase). 1[Ca 2ϩ ] e increased the activity of immunoprecipitated PI3Ј-kinase; moreover, PI3Ј-kinase inhibitors (wortmannin and LY294002) antagonized secretion. We suggest that PKC isoforms mediate secretion of 5-HT by PF cells in response to stimulation of the CaR. PKC involvement can be accounted for by PKC␥ and an isoform sensitive to inhibition by pseudoZ, probably PKC , which is activated via PI3Ј-kinase.

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“…This acid stimulatory effect of cinacalcet acting on both the G (42) and parietal cell (18) may warrant acid suppressive therapy to prevent cinacalcet intolerance caused by hyperacidity in vulnerable hemodialysis patients on long-term therapy for secondary hyperparathyroidism (43). The inhibition of gastrin secretion by NPS 2143 suggests that clinical trials of calcilytics for the treatment of osteoporosis should monitor potential deleterious inhibition of CaR on nonclassical Ca 2+ regulatory tissues (9,27,28).…”

Section: Deletion Of Car Does Not Significantly Alter the Gastrin Secmentioning

confidence: 99%

“…Although G-cell CaR expression and CaR-dependent response to extracellular Ca 2+ (8,16) suggest a direct chemosensory role, they do not preclude a role for neuronal CaR indirectly regulating the G cell. In fact, the rat gastric submucosal and myenteric neurons express CaR (9). GRP neuropetidesecreting intramural neurons project to the antral mucosa and stimulate gastrin secretion through G-cell GRPR-1 [bombesin subtype 1 receptor (BB1R)] receptors (45,46).…”

Section: G-cell Cars Are the Predominant Chemosensors Mediating Gastrinmentioning

confidence: 99%

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

Feng

Petersen²,

Coy³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca 2+ , whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca 2+ homeostatic capacity. Luminal nutrients, such as Ca 2+ and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca 2+ , amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca 2+ , peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca 2+ homeostasis should be reviewed for effects outside traditional Ca 2+ -regulating tissues in view of the broader distribution and function of CaR.

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Expression of an extracellular calcium-sensing receptor in rat stomach

Cited by 114 publications

References 23 publications

pH Sensing by the Calcium-sensing Receptor

pH Sensing by the Calcium-sensing Receptor

Ca²⁺-Evoked Serotonin Secretion by Parafollicular Cells: Roles in Signal Transduction of Phosphatidylinositol 3′-kinase, and the γ and ζ Isoforms of Protein Kinase C

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

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Expression of an extracellular calcium-sensing receptor in rat stomach

Cited by 114 publications

References 23 publications

pH Sensing by the Calcium-sensing Receptor

pH Sensing by the Calcium-sensing Receptor

Ca2+-Evoked Serotonin Secretion by Parafollicular Cells: Roles in Signal Transduction of Phosphatidylinositol 3′-kinase, and the γ and ζ Isoforms of Protein Kinase C

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

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Ca²⁺-Evoked Serotonin Secretion by Parafollicular Cells: Roles in Signal Transduction of Phosphatidylinositol 3′-kinase, and the γ and ζ Isoforms of Protein Kinase C