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Parathyroid Hormone and Polyhormones: Production and Export

Ruben Diaz, Ghada El‐Hajj Fuleihan, Edward M. Brown

10.1002/cphy.cp070316

Source: Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance

Originally published: 2000

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Role of Extracellular Calcium–Sensing and Extracellular Calcium–Regulated Parathyroid Hormone Secretion in Mineral ion Homeostasis
2 The G Protein–Coupled, Extracellular Calcium–Sensing Receptor
2.1 Structure and Function
2.2 Inherited Diseases Resulting from Receptor Mutations
2.3 Mice with Targeted Disruption of the Receptor
2.4 Are There Additional Receptors or Other Ion‐Sensing Receptors?
3 Anatomy and Physiology of the Parathyroid Cell
3.1 Morphology
3.2 Secretory Pathway
4 Physiological Control of Parathyroid Hormone Secretion by Extracellular Calcium and Other Factors
4.1 Acute Regulation
4.2 Additional Ionic Agonists Regulating Parathyroid Hormone Secretion via the Extracellular Calcium‐Sensing Receptor
4.3 Other Ions Modulating Parathyroid Hormone secretion
4.4 Rapid Actions of Vitamin D on Parathyroid Cells
4.5 Regulation of Parathyroid Hormone Secretion by Catecholamines and Other Biogenic Amines
4.6 Regulation of Parathyroid Hormone Secretion by Lipid Metabolites
4.7 Regulation of Parathyroid Hormone Secretion by Peptides and Peptide Hormones
4.8 Miscellaneous Factors Regulating Parathyroid Hormone Secretion
4.9 Mechanisms Underlying the Acute Regulation of Parathyroid Hormone Secretion by Extracellular Calcium
5 Regulation of Intracellular Degradation of Parathyroid Hormone
6 Regulation of Parathyroid Hormone Gene Expression
6.1 Chromosomal Localization and Organization of the Parathyroid Hormone Gene
6.2 Effects of Extracellular Calcium
6.3 Effects of Extracellular Phosphate
6.4 Effects of Vitamin D Metabolites
6.5 Parathyroid Hormone Regulation of Gene Expression by Steroids and Other Hormones
6.6 Regulation of Parathyroid Hormone Gene Expression by Agents that Increase Intracellular Cyclic Adenosine Monophosphate
6.7 Regulation of Overall Biosynthetic Activity of the Parathyroid Cell
7 Regulation of Parathyroid Cellular Proliferation
7.1 Effects of Extracellular Calcium
7.2 Effects of Vitamin D Metabolites
7.3 Effect of Extracellular Phosphate
7.4 Effect of Growth Factors
8 Circadian and Pulsatile Control of Parathyroid Hormone Secretion
8.1 Circadian Variation
8.2 Pulsatility
8.3 Alterations in Circadian Rhythm and Pulsatility in Patients with Abnormal Parathyroid Function
9 Secretion of Factors Other Than Parathyroid Hormone: Possible Autocrine/ Paracrine Regulation of Parathyroid Hormone Secretion
9.1 Evidence for Autocrine Control of Parathyroid Function
9.2 Secretion of Parathyroid Hormone–Related Protein
9.3 Secretion of Chromogranin A‐Derived Peptides
9.4 Secretion of Other Peptides
9.5 Secretion of Prostaglandins
Figure 1. Figure 1.

Steep inverse sigmoidal curves relating circulating parathyroid hormone (PTH) levels in vivo (top panel) and PTH release in vitro (bottom panel) to . Studies in vivo were performed in normal human subjects by administering EDTA on one day and calcium on another day intravenously and measuring circulating levels of intact PTH as a function of . Studies in vitro were carried out using dispersed parathyroid cells prepared from several different normal human parathyroid glands, each indicated by a different symbol. [From Brown 54 with permission.]
Figure 2. Figure 2.

The homeostatic system regulating . Even slight decrements in the level of stimulate parathyroid hormone (PTH) secretion, which then modulates the functions of bone, kidney, and intestine [indirectly through enhanced formation of 1,25(OH)2.D] to normalize . In addition to the actions of the classic calciotropic hormones, PTH and 1,25(OH)2.D (solid lines), extracellular calcium and phosphate ions exert direct actions (dashed lines). Some of the direct actions of are mediated by the ‐sensing receptor. PO4, phosphate; ECF, extracellular fluid; 1,25(OH)2D, 1,25–dihydroxyvitamin D; 25(OH)D, 25‐hydroxyvitamin D; + indicates stimulatory action and – inhibitory effect. [From Brown et al. 493 with permission.]
Figure 3. Figure 3.

Urinary excretion of calcium plotted as a function of total serum calcium concentration in normal human subjects (solid line) ± 2 SD (dashed lines) as well as in patients with hypoparathyroidism (triangles) and primary hyperparathyroidism (circles). [From Peacock et al. 344 with permission.]
Figure 4. Figure 4.

Predicted topology of the ‐sensing receptor from human parathyroid gland. Note the large extracellular domain, seven membrane‐spanning helices, and cytoplasmic C‐terminal tail. SP, signal peptide; HS, hydrophobic segment; PKC, protein kinase C. The positions of various missense and nonsense mutations causing either familial hypocalciuric hypercalcemia or autosomal dominant hypocalcemia are also indicated, using the three‐letter amino acid code, with the normal amino acid indicated before and the mutation after the number of the relevant codon. [From Brown et al. 492 with permission.]
Figure 5. Figure 5.

Effect of familial hypocalciuric hypercalcemia (FHH) on the relationship between serum and urinary calcium concentrations. Data are from either aparathyroid subjects who are otherwise normal (open symbols) or individuals with FHH who have been rendered hypoparathyroid following total parathyroidectomy (closed symbols). Note the marked flattening of this relationship in individuals with FHH, indicative of their failure to upregulate renal calcium excretion normally even in the face of substantial hypercalcemia. [From Attie et al. 14 with permission.]
Figure 6. Figure 6.

Expression in HEK 293 cells of ‐sensing receptors (CaRs) engineered to carry familial hypocalciuric hypercalcemia (top panel) or activating CaR mutations (bottom panel). Results show the effects of increasing concentrations of on levels of in HEK cells transiently transfected with wild‐type (WT) or mutant CaRs bearing the indicated mutations. [From Bai et al. 20 with permission.]
Figure 7. Figure 7.

Hypothetical ways in which the ‐sensing receptor integrates the homeostasis of divalent minerals, particularly calcium, and water to achieve the optimal “trade‐off” between the needs for conserving water and avoiding excessively high urinary calcium concentrations that might predispose to the formation of calcium‐containing stones within the distal urinary tract. [From Brown et al. 63 with permission.]
Figure 8. Figure 8.

Electron micrograph of parathyroid cells displaying cell polarity as revealed by the distribution of nuclei at the basal side, while secretory granules are preferentially located close to the apicolateral membrane, which is highlighted with the products of 5′‐nucleotidase activity, a well‐characterized enzyme marker for apical plasma membrane domains. Note the distinct characteristic folding of the apicolateral membrane in contrast to the basal plasma membrane juxtaposing the basal lamina. [From Wild and Schraner 494 with permission.]
Figure 9. Figure 9.

Possible pathways of parathyroid hormone (PTH) secretion in the parathyroid cell. The PTH gene is transcribed into mRNA coding for preproPTH in the nucleus. The preproPTH is synthesized in the cytosol and immediately translocated into the rough endoplasmic reticulum (RER), where the pre sequence is clipped. The proPTH is transported to the Golgi apparatus, where it stacks via a vesicle‐mediated pathway; the pro sequence is removed during transit to the trans‐Golgi network (TGN). Mature PTH is then packaged in immature secretory granules (ISG) in conjunction with chromo‐granin A (Cg A). Immature secretory granules can undergo maturation into larger, more dense mature secretory granules (MSG) by fusion to each other and condensation of the contents of their lumen; alternatively, immature secretory granules can release their contents directly at the plasma membrane or fuse to lysosomes (LYS), accelerating the time required to reach the cell surface or the degradation of PTH, respectively. Finally, it is possible that a fraction of PTH escapes packaging into immature secretory granules and reaches the plasma membrane via constitutive vesicles (CV), a pathway that is not regulated in most secretory cells and is present in all mammalian cells.
Figure 10. Figure 10.

A four‐parameter model of the relationship between parathyroid hormone (PTH) release and , which is based on the equation Y = {(A1 − D)/[1 + (X/C)B]} + D, where Y is the secretory rate for PTH and X is the extracellular free calcium ion concentration. The four parameters are as follows: A, maximal secretory rate; B, slope of the midpoint of the curve; C, midpoint or set‐point of the curve (defined as the level of that half‐maximally inhibits PTH secretion); and D, minimal secretory rate. [From Brown 53 with permission.]
Figure 11. Figure 11.

Temporal relationship between changes in and parathyroid hormone (PTH) secretion from perfused bovine parathyroid cells. [From Brown et al. 70 with permission.]
Figure 12. Figure 12.

Hysteresis in the relationship between circulating levels of intact parathyroid hormone (PTH) and serum ionized calcium concentration in normal human subjects during alterations in the direction of change of serum calcium concentration. Subjects were first infused with citrate to reduce the level of (solid triangles); then, the serum ionized calcium concentration was allowed to normalize (open triangles). On a subsequent day, the same subjects received an infusion of calcium to raise (solid circles), followed by citrate (open circles) to reduce back to its normal level. Note that on both days the serum PTH level is higher when is falling than when it is rising (that is, there is hysteresis). The vertical arrow indicates the basal levels of and PTH, while the other arrows show the direction in which is changing. [From Conlin et al. 100 with permission.]
Figure 13. Figure 13.

Apparent rate dependence in the response of circulating levels of intact parathyroid hormone (PTH) to stepwise decrements in induced by infusion of citrate to normal human subjects according to two different protocols. In one protocol (solid circles), citrate was first infused as a bolus followed at a constant rate for each of four 30 min periods. In the second (open circles), the initial bolus of citrate was omitted. As a result of the difference in the infusion protocols, there is a more rapid decrease in the level of to the eventual ∼0.05 mM decrement achieved at the end of each of the 30 min steps in the first protocol (A). This more rapid initial fall in elicits a more robust secretory response, which then decays to a level of PTH similar to that evoked by the second protocol at the end of each 30 min step (B). [From Grant et al. 170 with permission.]
Figure 14. Figure 14.

Potential intracellular pathways for regulation of parathyroid hormone (PTH) secretion in parathyroid cells. ISG, Immature secretory granule; MSG, mature secretory granule; PKC, protein kinase C; HETE, hydroxyeicosatetraenoic acid; PLA2, phospholipase A2; PLC, phospholipase C; D1R, dopamine 1 receptor; PAR, β‐adrenergic receptor; CaR, ‐sensing receptor. Solid lines represent pathways for which there is strong experimental evidence and dashed lines, pathways that have not been well characterized. Activation of the CaR in the presence of high raises G protein–mediated activation of PLC and inositol phosphate production and activation of a Ca2+ influx pathway, while cAMP levels decrease via pertussis toxin–sensitive inactivation of adenylate cyclase. Production of cAMP is stimulated in the presence of ligands for both βAR and D1,R. In addition, although total PKC activity is decreased in the presence of high , there is a CaR‐dependent activation of at least some PKC isoforms, which in turn activates PLA2 to produce HETEs, active metabolites of arachidonic acid produced by the lipoxygenase pathway. A rise in may also activate calpain, a protease that can inactivate some PKC isoforms, and contribute to the observed decrease in PKC activity at high . Activation of cAMP production is associated with increases in PTH secretion, derived primarily from the release of MSGs. Activation of PKC is also associated with increases in PTH secretion. Rises in and lipoxygenase metabolites of arachidonic acid (HETEs) are associated with inhibition of both ISG and MSG release. The mechanism that mediates the direct or indirect effects of these agents on inhibition of PTH secretion has not been characterized.


Figure 1.

Steep inverse sigmoidal curves relating circulating parathyroid hormone (PTH) levels in vivo (top panel) and PTH release in vitro (bottom panel) to . Studies in vivo were performed in normal human subjects by administering EDTA on one day and calcium on another day intravenously and measuring circulating levels of intact PTH as a function of . Studies in vitro were carried out using dispersed parathyroid cells prepared from several different normal human parathyroid glands, each indicated by a different symbol. [From Brown 54 with permission.]



Figure 2.

The homeostatic system regulating . Even slight decrements in the level of stimulate parathyroid hormone (PTH) secretion, which then modulates the functions of bone, kidney, and intestine [indirectly through enhanced formation of 1,25(OH)2.D] to normalize . In addition to the actions of the classic calciotropic hormones, PTH and 1,25(OH)2.D (solid lines), extracellular calcium and phosphate ions exert direct actions (dashed lines). Some of the direct actions of are mediated by the ‐sensing receptor. PO4, phosphate; ECF, extracellular fluid; 1,25(OH)2D, 1,25–dihydroxyvitamin D; 25(OH)D, 25‐hydroxyvitamin D; + indicates stimulatory action and – inhibitory effect. [From Brown et al. 493 with permission.]



Figure 3.

Urinary excretion of calcium plotted as a function of total serum calcium concentration in normal human subjects (solid line) ± 2 SD (dashed lines) as well as in patients with hypoparathyroidism (triangles) and primary hyperparathyroidism (circles). [From Peacock et al. 344 with permission.]



Figure 4.

Predicted topology of the ‐sensing receptor from human parathyroid gland. Note the large extracellular domain, seven membrane‐spanning helices, and cytoplasmic C‐terminal tail. SP, signal peptide; HS, hydrophobic segment; PKC, protein kinase C. The positions of various missense and nonsense mutations causing either familial hypocalciuric hypercalcemia or autosomal dominant hypocalcemia are also indicated, using the three‐letter amino acid code, with the normal amino acid indicated before and the mutation after the number of the relevant codon. [From Brown et al. 492 with permission.]



Figure 5.

Effect of familial hypocalciuric hypercalcemia (FHH) on the relationship between serum and urinary calcium concentrations. Data are from either aparathyroid subjects who are otherwise normal (open symbols) or individuals with FHH who have been rendered hypoparathyroid following total parathyroidectomy (closed symbols). Note the marked flattening of this relationship in individuals with FHH, indicative of their failure to upregulate renal calcium excretion normally even in the face of substantial hypercalcemia. [From Attie et al. 14 with permission.]



Figure 6.

Expression in HEK 293 cells of ‐sensing receptors (CaRs) engineered to carry familial hypocalciuric hypercalcemia (top panel) or activating CaR mutations (bottom panel). Results show the effects of increasing concentrations of on levels of in HEK cells transiently transfected with wild‐type (WT) or mutant CaRs bearing the indicated mutations. [From Bai et al. 20 with permission.]



Figure 7.

Hypothetical ways in which the ‐sensing receptor integrates the homeostasis of divalent minerals, particularly calcium, and water to achieve the optimal “trade‐off” between the needs for conserving water and avoiding excessively high urinary calcium concentrations that might predispose to the formation of calcium‐containing stones within the distal urinary tract. [From Brown et al. 63 with permission.]



Figure 8.

Electron micrograph of parathyroid cells displaying cell polarity as revealed by the distribution of nuclei at the basal side, while secretory granules are preferentially located close to the apicolateral membrane, which is highlighted with the products of 5′‐nucleotidase activity, a well‐characterized enzyme marker for apical plasma membrane domains. Note the distinct characteristic folding of the apicolateral membrane in contrast to the basal plasma membrane juxtaposing the basal lamina. [From Wild and Schraner 494 with permission.]



Figure 9.

Possible pathways of parathyroid hormone (PTH) secretion in the parathyroid cell. The PTH gene is transcribed into mRNA coding for preproPTH in the nucleus. The preproPTH is synthesized in the cytosol and immediately translocated into the rough endoplasmic reticulum (RER), where the pre sequence is clipped. The proPTH is transported to the Golgi apparatus, where it stacks via a vesicle‐mediated pathway; the pro sequence is removed during transit to the trans‐Golgi network (TGN). Mature PTH is then packaged in immature secretory granules (ISG) in conjunction with chromo‐granin A (Cg A). Immature secretory granules can undergo maturation into larger, more dense mature secretory granules (MSG) by fusion to each other and condensation of the contents of their lumen; alternatively, immature secretory granules can release their contents directly at the plasma membrane or fuse to lysosomes (LYS), accelerating the time required to reach the cell surface or the degradation of PTH, respectively. Finally, it is possible that a fraction of PTH escapes packaging into immature secretory granules and reaches the plasma membrane via constitutive vesicles (CV), a pathway that is not regulated in most secretory cells and is present in all mammalian cells.



Figure 10.

A four‐parameter model of the relationship between parathyroid hormone (PTH) release and , which is based on the equation Y = {(A1 − D)/[1 + (X/C)B]} + D, where Y is the secretory rate for PTH and X is the extracellular free calcium ion concentration. The four parameters are as follows: A, maximal secretory rate; B, slope of the midpoint of the curve; C, midpoint or set‐point of the curve (defined as the level of that half‐maximally inhibits PTH secretion); and D, minimal secretory rate. [From Brown 53 with permission.]



Figure 11.

Temporal relationship between changes in and parathyroid hormone (PTH) secretion from perfused bovine parathyroid cells. [From Brown et al. 70 with permission.]



Figure 12.

Hysteresis in the relationship between circulating levels of intact parathyroid hormone (PTH) and serum ionized calcium concentration in normal human subjects during alterations in the direction of change of serum calcium concentration. Subjects were first infused with citrate to reduce the level of (solid triangles); then, the serum ionized calcium concentration was allowed to normalize (open triangles). On a subsequent day, the same subjects received an infusion of calcium to raise (solid circles), followed by citrate (open circles) to reduce back to its normal level. Note that on both days the serum PTH level is higher when is falling than when it is rising (that is, there is hysteresis). The vertical arrow indicates the basal levels of and PTH, while the other arrows show the direction in which is changing. [From Conlin et al. 100 with permission.]



Figure 13.

Apparent rate dependence in the response of circulating levels of intact parathyroid hormone (PTH) to stepwise decrements in induced by infusion of citrate to normal human subjects according to two different protocols. In one protocol (solid circles), citrate was first infused as a bolus followed at a constant rate for each of four 30 min periods. In the second (open circles), the initial bolus of citrate was omitted. As a result of the difference in the infusion protocols, there is a more rapid decrease in the level of to the eventual ∼0.05 mM decrement achieved at the end of each of the 30 min steps in the first protocol (A). This more rapid initial fall in elicits a more robust secretory response, which then decays to a level of PTH similar to that evoked by the second protocol at the end of each 30 min step (B). [From Grant et al. 170 with permission.]



Figure 14.

Potential intracellular pathways for regulation of parathyroid hormone (PTH) secretion in parathyroid cells. ISG, Immature secretory granule; MSG, mature secretory granule; PKC, protein kinase C; HETE, hydroxyeicosatetraenoic acid; PLA2, phospholipase A2; PLC, phospholipase C; D1R, dopamine 1 receptor; PAR, β‐adrenergic receptor; CaR, ‐sensing receptor. Solid lines represent pathways for which there is strong experimental evidence and dashed lines, pathways that have not been well characterized. Activation of the CaR in the presence of high raises G protein–mediated activation of PLC and inositol phosphate production and activation of a Ca2+ influx pathway, while cAMP levels decrease via pertussis toxin–sensitive inactivation of adenylate cyclase. Production of cAMP is stimulated in the presence of ligands for both βAR and D1,R. In addition, although total PKC activity is decreased in the presence of high , there is a CaR‐dependent activation of at least some PKC isoforms, which in turn activates PLA2 to produce HETEs, active metabolites of arachidonic acid produced by the lipoxygenase pathway. A rise in may also activate calpain, a protease that can inactivate some PKC isoforms, and contribute to the observed decrease in PKC activity at high . Activation of cAMP production is associated with increases in PTH secretion, derived primarily from the release of MSGs. Activation of PKC is also associated with increases in PTH secretion. Rises in and lipoxygenase metabolites of arachidonic acid (HETEs) are associated with inhibition of both ISG and MSG release. The mechanism that mediates the direct or indirect effects of these agents on inhibition of PTH secretion has not been characterized.

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Article Title: Parathyroid Hormone and Polyhormones: Production and Export
 

How to Cite

Ruben Diaz, Ghada El‐Hajj Fuleihan, Edward M. Brown. Parathyroid Hormone and Polyhormones: Production and Export. Compr Physiol 2011, Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance: 605-662. First published in print 2000. doi: 10.1002/cphy.cp070316