Calcium-Ion–Sensing Cell-Surface Receptors

Brown, Edward M.; Pollak, Martin R.; Seidman, Christine E.; Seidman, Jonathan G.; Chou, Ya-Huei Wu; Riccardi, Daniela; Hebert, Steven C.

doi:10.1056/nejm199507273330407

Cited by 225 publications

(154 citation statements)

References 50 publications

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“…Inositol Trisphosphate Production in Response to Activation of the CaR-Activation of the CaR has been demonstrated to result in increased production of IP 3 (10,21). To determine whether the CaR agonist Gd 3ϩ could induce IP 3 production in rat fibroblasts, we measured IP 3 production directly in response to 250 M Gd 3ϩ as described previously (18).…”

Section: Expression Of Functional Car In Rat-1 Fibroblastsmentioning

confidence: 99%

Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium

McNeil¹,

Hobson

Nipper

et al. 1998

Journal of Biological Chemistry

212

124

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Changes in the concentration of extracellular calcium can affect the balance between proliferation and differentiation in several cell types, including keratinocytes, breast epithelial cells, and fibroblasts. This report demonstrates that elevation of extracellular calcium stimulates proliferation-associated signaling pathways in rat fibroblasts and implicates calcium-sensing receptors (CaR) as mediators of this response. Rat-1 fibroblasts express CaR mRNA and protein and respond to known agonists of the CaR with increased IP 3 production and release of intracellular calcium. Agonists of the CaR can stimulate increased c-SRC kinase activity and increased extracellular signal-regulated kinase 1/mitogen-activated protein kinase activity. Both of the increases in SRC activity and mitogen-activated protein kinase activation are blocked in the presence of a nonfunctional mutant of the CaR, R796W. Proliferation of wild-type Rat-1 cells is sensitive to changes in extracellular calcium, but expression of the nonfunctional CaR mutant or inhibition of the calcium-dependent increase in SRC kinase activity block the proliferative response to calcium. These results provide evidence of a novel signal transduction pathway modulating the response of fibroblasts to extracellular calcium and imply that calciumsensing receptors may play a role in regulating cell growth in response to extracellular calcium, in addition to their well known function in systemic calcium homeostasis.

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Section: Expression Of Functional Car In Rat-1 Fibroblastsmentioning

confidence: 99%

Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium

McNeil¹,

Hobson

Nipper

et al. 1998

Journal of Biological Chemistry

212

124

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“…A single parathyroid adenoma is the most common cause of PHPT (1), but the pathogenesis of these lesions is poorly understood. Altered calcium-sensing receptor (CASR)-mediated control of PTH secretion with the consequent increased parathyroid cell proliferation is fundamental to the development of PHPT (2,3). In addition, 1,25-dihydroxyvitamin D, through its interactions with vitamin D receptor (VDR) in parathyroid cells, modulates parathyroid function and growth (4,5,6,7,8).…”

Section: Introductionmentioning

confidence: 99%

Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians

Varshney

Bhadada

Saikia

et al. 2013

European Journal of Endocrinology

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Background: To explore underlying molecular mechanisms in the pathogenesis of symptomatic sporadic primary hyperparathyroidism (PHPT). Materials and methods: Forty-one parathyroid adenomas from patients with symptomatic PHPT and ten normal parathyroid glands either from patients with PHPT (nZ3) or from euthyroid patients without PHPT during thyroid surgery (nZ7) were analyzed for vitamin D receptor (VDR), calcium-sensing receptor (CASR), cyclin D1 (CD1), and parathyroid hormone (PTH) expressions. The protein expressions were assessed semiquantitatively by immunohistochemistry, based on percentage of positive cells and staining intensity, and confirmed by quantitative real-time PCR. Results: Immunohistochemistry revealed significant reductions in VDR (both nuclear and cytoplasmic) and CASR expressions and significant increases in CD1 and PTH expressions in adenomatous compared with normal parathyroid tissue. Consistent with immunohistochemistry findings, both VDR and CASR mRNAs were reduced by 0.36-and 0.45-fold change (P!0.001) and CD1 and PTH mRNAs were increased by 9.4-and 17.4-fold change respectively (P!0.001) in adenomatous parathyroid tissue. PTH mRNA correlated with plasma PTH (rZ0.864; P!0.001), but not with adenoma weight, while CD1 mRNA correlated with adenoma weight (rZ0.715; P!0.001). There were no correlations between VDR and CASR mRNA levels and serum Ca, plasma intact PTH, or 25-hydroxyvitamin D levels. In addition, there was no relationship between the decreases in VDR and CASR mRNA expressions and the increases in PTH and CD1 mRNA expressions. Conclusions: The expression of both VDR and CASR are reduced in symptomatic PHPT in Asian Indians. In addition, CD1 expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth and differential clinical expression of PHPT.

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“…The function of CasR in other tissues is less clear. In the kidney, CasR may modulate renal tubular transport, possibly acting as an antagonist to parathyroid hormone actions on renal calcium handling (7). CasR is also located in nerve terminals, where it may transduce calcium-mediated neurotransmitter release (3).…”

mentioning

confidence: 99%

“…CasR is also located in nerve terminals, where it may transduce calcium-mediated neurotransmitter release (3). CasR is detected in low abundance in many other tissues and cell types, where its physiologic role is uncertain (7)(8)(9).…”

mentioning

confidence: 99%

Sensing of Extracellular Cations in CasR-deficient Osteoblasts

Garner

Flannery

et al. 2000

Journal of Biological Chemistry

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We isolated osteoblastic cell lines from wild-type (CasR ؉/؉ ) and receptor null (CasR ؊/؊ ) mice to investigate whether CasR is present in osteoblasts and accounts for their responses to extracellular cations. Osteoblasts from both CasR ؉/؉ and CasR ؊/؊ mice displayed an initial period of cell replication followed by a culture duration-dependent increase in alkaline phosphatase activity, expression of osteocalcin, and mineralization of extracellular matrix. In addition, a panel of extracellular cations, including aluminum and the CasR agonists gadolinium and calcium, stimulated DNA synthesis, activated a transfected serum response elementluciferase reporter construct, and inhibited agonistinduced cAMP in CasR ؊/؊ osteoblasts. The functional responses to these cations were identical in CasR ؉/؉ and CasR ؊/؊ osteoblasts. Thus, the absence of CasR alters neither the maturational profile of isolated osteoblast cultures nor their in vitro responses to extracellular cations. In addition, CasR transcripts could not be detected by reverse transcription-polymerase chain reaction with mouse specific primers in either CasR ؉/؉ or CasR ؊/؊ osteoblasts, and immunoblot analysis with a CasR-specific antibody was negative for CasR protein expression in osteoblasts. The presence of a cation-sensing response in osteoblasts from CasR ؊/؊ mice indicates the existence of a novel osteoblastic extracellular cation-sensing mechanism.

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Calcium-Ion–Sensing Cell-Surface Receptors

Cited by 225 publications

References 50 publications

Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium

Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium

Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians

Sensing of Extracellular Cations in CasR-deficient Osteoblasts

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