Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism.

KL Campion, WD McCormick, J Warwicker, ME Khayat, R Atkinson-Dell, MC Steward, LW Delbridge, HC Mun, AD Conigrave, DT Ward

    Research output: Contribution to journalArticleResearchpeer-review

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    Abstract

    The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca2+i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca2+o). Similar pHo effects were observed for Ca2+o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca2+i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo.
    Original languageEnglish
    Pages (from-to)2163
    Number of pages2171
    JournalJournal of the American Society of Nephrology
    Volume26
    Issue number9
    Early online date2 Jan 2015
    DOIs
    Publication statusPublished - Sep 2015

    Fingerprint

    Calcium-Sensing Receptors
    Histidine
    Parathyroid Hormone
    Calcium
    HEK293 Cells
    Acidosis
    Alkalosis
    Secondary Hyperparathyroidism
    Extracellular Signal-Regulated MAP Kinases
    Point Mutation
    Polymerization
    Cysteine
    Actins
    Albumins
    Phosphorylation

    Keywords

    • calcium-sensing receptor
    • parathyroid hormone
    • hyperparathyroidism
    • acidosis
    • mineral metabolism

    Cite this

    Campion, KL ; McCormick, WD ; Warwicker, J ; Khayat, ME ; Atkinson-Dell, R ; Steward, MC ; Delbridge, LW ; Mun, HC ; Conigrave, AD ; Ward, DT. / Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 9. pp. 2163.
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    abstract = "The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca2+i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca2+o). Similar pHo effects were observed for Ca2+o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca2+i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo.",
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    Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism. / Campion, KL; McCormick, WD; Warwicker, J; Khayat, ME; Atkinson-Dell, R; Steward, MC; Delbridge, LW; Mun, HC; Conigrave, AD; Ward, DT.

    In: Journal of the American Society of Nephrology, Vol. 26, No. 9, 09.2015, p. 2163.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism.

    AU - Campion, KL

    AU - McCormick, WD

    AU - Warwicker, J

    AU - Khayat, ME

    AU - Atkinson-Dell, R

    AU - Steward, MC

    AU - Delbridge, LW

    AU - Mun, HC

    AU - Conigrave, AD

    AU - Ward, DT

    PY - 2015/9

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    N2 - The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca2+i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca2+o). Similar pHo effects were observed for Ca2+o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca2+i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo.

    AB - The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca2+i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca2+o). Similar pHo effects were observed for Ca2+o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca2+i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo.

    KW - calcium-sensing receptor

    KW - parathyroid hormone

    KW - hyperparathyroidism

    KW - acidosis

    KW - mineral metabolism

    UR - http://europepmc.org/abstract/med/25556167

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    DO - 10.1681/asn.2014070653

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