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 JournalArticle

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 JournalArticle

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

Y1 - 2015/9

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

U2 - 10.1681/asn.2014070653

DO - 10.1681/asn.2014070653

M3 - Article

C2 - 25556167

VL - 26

SP - 2163

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1533-3450

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ER -