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The Regulation of Parathyroid Hormone Secretion and Synthesis Rajiv Kumar* and James R. Thompson† *Division of Nephrology and Hypertension, Department of Internal Medicine, Biochemistry and Molecular Biology, and †Department of Physiology, Biophysics and Bioengineering, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota

ABSTRACT Secondary hyperparathyroidism classically appears during the course of chronic renal failure and sometimes after renal transplantation. Understanding the mechanisms by which parathyroid hormone (PTH) synthesis and secretion are normally regulated is important in devising methods to regulate overactivity and hyperplasia of the parathyroid gland after the onset of renal insufficiency. Rapid regulation of PTH secretion in response to variations in serum calcium is mediated by G-protein coupled, calciumsensing receptors on parathyroid cells, whereas alterations in the stability of mRNAencoding PTH by mRNA-binding proteins occur in response to prolonged changes in serum calcium. Independent of changes in intestinal calcium absorption and serum calcium, 1␣,25-dihydroxyvitamin D also represses the transcription of PTH by associating with the vitamin D receptor, which heterodimerizes with retinoic acid X receptors to bind vitamin D-response elements within the PTH gene. 1␣,25-Dihydroxyvitamin D additionally regulates the expression of calcium-sensing receptors to indirectly alter PTH secretion. In 2°HPT seen in renal failure, reduced concentrations of calciumsensing and vitamin D receptors, and altered mRNA-binding protein activities within the parathyroid cell, increase PTH secretion in addition to the more widely recognized changes in serum calcium, phosphorus, and 1␣,25-dihydroxyvitamin D. The treatment of secondary hyperparathyroidism by correction of serum calcium and phosphorus concentrations and the administration of vitamin D analogs and calcimimetic agents may be augmented in the future by agents that alter the stability of mRNA-encoding PTH.

basis of these observations regarding pathogenesis, therapy for 2°HPT in the context of CKD and ESRD includes the control of serum phosphate concentrations, the administration of Ca2⫹ and vitamin D analogs, and the administration of calcimimetics.33,34,16,35,36 Nevertheless, 2°HPT remains a significant clinical problem and additional methods for the treatment of this condition would be helpful, especially in refractory situations, where other measures have failed or are only partially effective. Knowledge about the mechanisms by which parathyroid hormone secretion and synthesis occur is therefore of value in designing new approaches to the treatment of this condition. Here we briefly review the mechanisms that modulate PTH release and secretion and identify abnormalities that are present in progressive renal disease.

J Am Soc Nephrol 22: 216 –224, 2011. doi: 10.1681/ASN.2010020186

The central role of the parathyroid glands in regulating Ca2⫹ homeostasis by modulating bone metabolism, the synthesis of 1␣,25-dihydroxyvitamin D (1␣,25(OH)2D) in proximal tubules, and the reabsorption of Ca2⫹ in the distal nephron is widely appreciated by the readers of this journal.1–5 Secondary hyperparathyroidism (2°HPT) frequently occurs in the setting of chronic kidney disease (CKD), of end-stage renal disease (ESRD), or after renal transplantation,6–12 and uncontrolled 2°HPT in CKD and ESRD associates with an in216

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creased incidence of fractures and mortality.13–16 The pathogenesis of 2°HPT in CKD is complex. Phosphate retention, hyperphosphatemia, low serum Ca2⫹ (sCa2⫹), elevated levels of parathyroid hormone (PTH), 1␣,25(OH)2D deficiency, intestinal Ca2⫹ malabsorption, the reduction of vitamin D receptors (VDR) and calcium-sensing receptors (CaSR) in the parathyroid glands, and altered mRNA-binding protein activities modulating PTH transcripts play a role in the development of 2°HPT.17–30 Parathyroid hyperplasia is often present as well.31,32 On the

PTH RELEASE AND SYNTHESIS DETERMINE SERUM PTH CONCENTRATIONS

Serum PTH concentrations are dependent upon the release of PTH stored in Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Rajiv Kumar, Division of Nephrology and Hypertension, Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic and Foundation, 200 1st Street SW, Rochester, MN 55905. Phone: 507-284-0020; Fax: 507-5389536; E-mail: [email protected] Copyright © 2011 by the American Society of Nephrology

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secretory granules within the parathyroid gland and by the synthesis of new PTH.1,37 sCa2⫹, phosphorus, and vitamin D metabolites play a role in regulating PTH release and synthesis.1,3,28,38 – 41 RapidPTHreleasefromsecretorygranulesin hypocalcemic states is modulated by the binding of Ca2⫹ to CaSRs on chief cells, whereas long-term replenishment of PTH stores is dependent on new PTH synthesis that is controlled by the availability of mRNA-encoding PTH for ribosomal translation into prepro-PTH.2,42,43,27,44–49 Hypocalcemia also retards the rate of degradation of PTH within the parathyroid gland, thus making more PTH available for release,50,51 and increases cell division in the parathyroid gland possibly through the action of the CaSR.1,42,45,52 Phosphorus additionally alters PTH synthesis, although the precise mechanisms by which changes in phosphate concentrations are detected or sensed by the parathyroid gland are unknown.28 1␣,25-Dihydroxyvitamin D (1␣,25(OH)2D) alters the transcription of PTH and may have an indirect effect on PTH release by increasing the expression of CaSR.38 – 41,45,53–56

ROLE OF THE CASR IN MEDIATING PTH RELEASE

Changes in concentrations of sCa2⫹ are sensed by chief cells through a cell-surface, seven-transmembrane, G protein– coupled receptor, the CaSR,42,57–59 and receptor activity results in rapid alterations in PTH secretion.37 After the induction of abrupt and sustained hypocalcemia, plasma concentrations of PTH increase within 1 minute, peak at 4 to 10 minutes, and thereafter decline gradually to approximately 60% of the maximum at 60 minutes, despite ongoing and constant hypocalcemia. Abrupt restoration of normocalcemia from the hypocalcemic state causes levels of PTH to decrease with an apparent half-life of approximately 3 minutes. In addition to its role in the parathyroid gland, the CaSR plays an important role in regulating Ca2⫹ reabsorption in the thick ascending limb of the loop of Henle.60 – 62 The vital role of the CaSR in Ca2⫹ hoJ Am Soc Nephrol 22: 216 –224, 2011

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Figure 1. A hypothetical dimeric model of residues D23 (blue) to I528 (red) of the human calcium sensing receptor extracellular domain (CaSR ECD). (A) Both monomers containing just the Venus flytrap region of the CaSR ECD are shown in a closed and presumably active conformation as was reported for the extracellular domain of the glutamate receptor with glutamate bound. The two yellow spheres (yellow arrows) indicate putative Ca2⫹-binding sites, found at the nexus of where both lobes of a monomer meet. Most residues forming this cation-binding site are not conserved in glutamate receptor. The additional cyan spheres within the topmost lobes of the dimer designate possible Mg2⫹-binding sites (green spheres indicated by green arrows) brought over from glutamate receptor coordinates. These Mg2⫹ sites are completely conserved in CaSR. The dimer interface of the portion of CaSR shown is completely formed from interactions between these two upper lobes. There are no intermolecular disulfide bridges linking the dimer together within this portion of the ECD of CaSR, although two intramolecular disulfides exist. (B) A model of the apo-CaSR dimer is portrayed. Again, the color ramps from blue to red from D23 to I528. The Mg2⫹ sites are present, although there is no experimental basis for this premise. Of note is the significant opening and expansion of the cavities between the upper and lower lobes of each monomer, the areas indicated by the two yellow ovals. (C) The upper lobes of the CaSR atomic coordinates shown above in (A) (with Ca2⫹ bound, now made gray in color) are superimposed on the apo-form model for the CaSR dimer drawn in rainbow as in (B). The red arrows point to a large displacement in the orientation and position of the carboxyterminal end of the structure near where the CaSR cysteine-rich domains (not shown) might be found. Significant conformational changes within parts of the CaSR ECD connecting with the transmembrane domains probably occur on Ca binding.

meostasis is demonstrated by the biologic consequences of inactivating or activating mutations of the receptor. Inactivating mutations of the CaSR result in familial benign hypercalcemia or neonatal severe hyperparathyroidism, whereas activating mutations result in autosomal dominant hypocalcemia.62,63,53,64 – 68 The CaSR has a large extracellular domain of approximately 600 amino acids, a seven-pass transmembrane domain, and an intracellular carboxyl-terminal domain that has several phosphorylation sites.69 The receptor binds Ca2⫹ in its extracellular domain, most likely as a dimer in the so-called “Venus flytrap” configuration (Figure 1, A through C).70 –73 Our model of the human CaSR shown in Figure 1 was obtained using multiple sequence alignments and initial coordinate models and two separate algorithms.74 –77 The best model resulted from using the extracellular domain of the glutamate receptor (Protein Data Bank code

1ewk)78 as the template for main chain atoms. The atomic coordinates within the model were inspected and manually corrected for steric clashes, for alternative residue rotamer choices that improve hydrogen bonding, and for Ramachandran and other conformational outliers. The CaSR dimer from D23 to I528 displays perfect twofold symmetry similar to that of the glutamate receptor bound with both glutamate and gadolinium ions.79 The putative Ca2⫹-binding sites were included in our CaSR model based on the presence of Gd2⫹ atomic coordinates within other glutamate receptor structures (PDBs 1ewk and 1isr). In the glutamate receptor, the Gd2⫹ location occurs at an acidic patch, including the ligating residues E238, D215, and E224 with one standout residue R220. The acidic residues of equivalent positions in CaSR are conserved, although an arginine residue is not conserved. Therefore, it is likely that the Ca2⫹-binding poPTH Secretion and Synthesis

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sition in the glutamate receptor and the CaSR are similar. When Ca2⫹ binds to the CaSR, it elicits a conformational change within the extracellular domain of the receptor (compare Figure 1B with Figure 1C). These changes are possibly transmitted through the seven-pass transmembrane domain to allow interactions of the intracellular domains of the receptor with heterotrimeric G protein subunits, Gqa and Gia. In addition to Ca2⫹, the CaSR binds several metals, amino acids, antibiotics, and organic compounds that modulate its activity (Figure 2).80 – 85 For modeling of phenylalanine and neomycin, coordinates were docked into our model of CaSR manually, maximizing the number of hydrogen bonds while minimizing the number of steric clashes. Agents such as L-amino acids with aromatic side chains exert allosteric effects on the CaSR and sensitize it to the effects of agonists such as Ca2⫹.80,81,86 – 89 These

Figure 2. Models of bound phenylalanine and neomycin molecules within the cavities of the CaSR dimer. (A) Above the predicted Ca2⫹-binding sites shown by yellow spheres are phenylalanine molecules shown in a conformation that stacks its side-chain ring against a tryptophan residue that is unique to CaSR, whereas remaining atoms occupy the same locations as found for the glutamate molecules bound to glutamate receptor. (B) Two neomycin molecules may also be docked within a third buried location as shown in the bottom-most image. 218

substances (“calcimimetic” agents) potentiate the CaSR to subthreshold concentrations of Ca2⫹. Several synthetic CaSR modulators have been developed for the treatment of hyperparathyroidism. NPS-R-467 and NPS-R-568 (phenylalkylamines) are examples of allosteric activators of the CaSR. Cinacalcet (Sensipar) is an example of a calcimimetic phenylalkylamine used to reduce PTH secretion that is now increasingly used in the treatment of 2°HPT in renal disease and in primary hyperparathyroidism.90 –92 Other compounds, known as “calcilytic” agents, block the CaSR and allow the release of increased amounts of PTH from the parathyroid gland for any given sCa2⫹ concentration.83,93–95 These agents, when administered intermittently, could be useful for the treatment of osteoporosis.83,93–95 When extracellular Ca2⫹ binds to the CaSR, it elicits conformational changes within the receptor. The heterotrimeric G protein subunits, Gqa and Gia, are recruited to the receptor and alter the amounts or activity of several intracellular mediators including Ca2⫹, cAMP, and phospholipases within the chief cell (Figure 3).42,59,70 Intracellular Ca2⫹ is altered as a result of activation of phospholipase C (PLC) by the Gq␣ subunit of the heterotrimeric G proteins. This results in the PLC-mediated hydrolysis of phosphatidylinositol-4,5,-bisphosphate and the resultant formation of inositol 1,4,5trisphosphate and diacylglycerol. 1,4,5Trisphosphate mobilizes intracellular Ca2⫹ stores by binding to its cognate receptor. The CaSR also interacts with Gi␣ to inhibit adenylate cyclase activity that reduces intracellular cyclic AMP.42 In addition, activation of PLA2 results in the production of arachidonic acid and activation of phophatidylinositol 4-kinase which replenishes phosphatidylinositol4,5,-bisphosphate.42,59,70 These changes within chief cells rapidly enhance the release of preformed PTH from the parathyroid gland. In addition to controlling PTH release and modulating Ca2⫹ flux in the kidney, the CaSR also plays a role in the control of cellular differentiation, cellular growth, and apoptosis.96 CaSRs acti-

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vate signaling pathways that regulate cellular growth through MAPKs, ERKs, and JNK kinases.96 –100 The binding of CaSRs to intracellular scaffolding proteins such as filamin A is important in mediating this effect.97,101–108 The CaSR interacts with filamin A to create a scaffold necessary for the organization of Gq␣, Rho guanine nucleotide exchange factor, and Rho signaling pathways.55 The affinity of the CaSR for filamin A is greater in the presence of Ca2⫹.104 Filamin A protects the CaSR from degradation,104 and silencing filamin A expression with siRNAs inhibits CaSR signaling.101 CaSR activation increases the activity of a serum-response element by increasing the membrane localization of the Rho protein.55 Transcription of the CaSR is not influenced by Ca2⫹ concentrations but is altered in vivo by 1␣,25(OH)2D in the parathyroid gland, in the kidney, and in thyroid C cells.24,55,54,56 Vitamin D response elements have been identified in the two promoter regions (P1 and P2), 380 and 160 bp upstream of the transcription start sites of the CaSR gene, respectively.55 These vitamin D response elements are atypical hexameric repeats that are separated by three nucleotides. In CKD, CaSR amounts are reduced in the parathyroid gland, most likely as a result of hyperplasia and perhaps as a result of reduced serum 1␣,25(OH)2D concentrations.109–112 The reductions in CaSR concentrations in the parathyroid gland attenuate the responsiveness of the gland to sCa2⫹ and contribute to 2°HPT.

THE REGULATION OF PTH SYNTHESIS

As noted earlier, replenishment of PTH stores after the release of preformed PTH is dependent on the synthesis of new preproPTH by ribosomes.1,2,43 This is dependent, in turn, upon the availability of mRNAencoding PTH. As we discuss in the sections that follow, changes in mRNA concentrations are the result of changes in PTH gene transcription or mRNA stability. J Am Soc Nephrol 22: 216 –224, 2011

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Figure 3. Pathways by which the CaSR homodimer signals in cells after binding of Ca2⫹ to the extracellular domains (red line) of the CaSR molecules in the homodimeric pair. Through the association of the CaSR with the i-type heterotrimeric G protein, Gi␣, adenylate cyclase (AC) activity is inhibited and cyclic AMP (cAMP) concentrations decrease. Association of the CaSR with the Gq␣ subunit of q-type heterotrimeric G protein results in the activation of PLC that increases inositol (1,4,5)P3 and diacylglycerol (DAG) with attendant downstream effects such as an increase in intracellular calcium that is mobilized from intracellular stores, and the activation of PKC. MAPK and PLA2 are activated by Gq␣-dependent pathways with increases in MEK and ERK and an increase in arachidonic acid formation.

Transcriptional Regulation of mRNA-Encoding PTH

The rate of transcription of the PTH gene is repressed by 1␣,25(OH)2D.38,39,41,45 1␣,25(OH)2D binds to the VDR receptor and the liganded VDR, in association with the retinoic acid X receptor (RXR), binds to a vitamin D response element within the promoter region of the PTH gene.113 Structurally,thisresponseelementresemblesthose found in other genes that are upregulated by 1␣,25(OH)2D. Reduced 1␣,25(OH)2D concentrations in CKD or ESRD, as well as reduced VDR concentrations within the parathyroid gland, contribute to 2°HPT.23 Role of RNA-Binding Proteins in the Regulation of mRNA-Encoding PTH by Changing mRNA Stability

When sCa2⫹ concentrations decrease, levels of mRNA-encoding PTH increase within the parathyroid gland.46,47 Surprisingly, changes in mRNA synthesis in response to decreases in sCa2⫹ are not due to changes in PTH gene transcription.28,27,44,48,49 Rather, levels of bovine and murine mRNA-encoding pth are regulated by proteins that bind elements J Am Soc Nephrol 22: 216 –224, 2011

within the 3⬘-untranslated region that influence mRNA stability.28,27,44,48,49 By way of background, after transcription, nascent RNA undergoes 5⬘methyl capping, splicing, cleavage, and polyadenylation in the nucleus (Figure 4A).114 –117 After export from the nucleus, mRNA transcripts interact with RNA-binding proteins that influence RNA half-life and stability within the cell (Figure 4A).95,118 –120 RNA-binding proteins interact with sequence-specific elements, adenine- and uridine-rich elements (AREs), that are usually present within the 3⬘-untranslated regions (3⬘UTRs) of RNA and regulate the rate at which mRNAs are translated or degraded in cells.121,114,122–124 The fate of an mRNA species containing an ARE bound to ARE-binding proteins is partly dependent upon the relative amounts of different bound stabilizing or destabilizing ARE-binding proteins. AREs have a variable structure: Class I AREs contain several copies of the AUUUA motif dispersed within U-rich regions; Class II AREs possess at least two overlapping UUAUUUA(U/A)nonamers;ClassIIIAREs

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are less well-defined and generally do not contain an AUUUA sequence.125,114,122 As shown in Figure 4A, RNAs targeted for degradation undergo deadenylation, decapping, and degradation in a large multiprotein complex, the exosome, or in cytoplasmic compartments known as GW bodies or processing bodies (P-bodies).126 –128 A 63-nucleotide ARE in the 3⬘-UTR of murine mRNA-encoding PTH, comprised of a core 26-nucleotide minimal binding sequence and adjacent flanking regions, regulates mRNA stability in response to changes in Ca2⫹ and phosphate concentrations.28,44,129 The ARE in the 3⬘-UTR of mRNA-encoding PTH binds two proteins, AU-rich element– binding protein 1 (AUF1) and K-homology splicing regulatory protein (KSRP).27,29 AUF1 increases mRNA halflife, whereas KSRP has the opposite effect.27,29 Both proteins are regulated by changes in sCa2⫹ and phosphate and are altered in CKD.27,30,130 The Bioactivity of KSRP Is Altered by Other Intracellular Enzymes

Peptidyl-prolyl cis-trans isomerase, NIMAinteracting-1 (Pin1), a peptidyl-prolyl isomerase,altersKSRPphosphorylationandthe binding of KSRP to the AREs in mRNA-encoding PTH. Pin1 binds to KSRP and prevents the phosphorylation of KSRP at serine residue 181. Nonphosphorylated KSRP is active and enhances degradation of mRNA-encoding PTH (Figure 4B). Pin1 specifically binds serine/threonine–protein motifs and catalyzes the cis-trans isomerization of peptide bonds, thereby changing the activity of proteins. Pin1 interacts with AUF1 and stabilizes mRNA-encoding GMCSF and TGFB.131,132 Interestingly, Pin1 epitopes and Pin1 enzymatic activity are detectable in rat parathyroid glands and parathyroid extracts.30 In heterologous cell systems, inhibition of Pin1 activity, or knockdown of Pin1 expression, increases mRNA-encoding PTH by inhibiting degradation, whereas overexpression of Pin1 reduces mRNA-encoding PTH by accelerating its decay. Pin1 null mice have increased levels of PTH in the parathyroid gland and circulating serum PTH concentrations without changes in sCa2⫹ and phosphate levels. Induction of 2°HPT by feeding rats PTH Secretion and Synthesis

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Figure 4. (A) Cellular processing of mRNA. Nascent mRNA comprised of exons (E1 through E4) and intervening sequences (IVS) is processed in the nucleus by 5⬘-methyl capping, splicing, cleavage, and polyadenylation. In the cytoplasm, AU-rich element– binding proteins (ARE-BPs, blue box and red oval) bind to AREs within the 3⬘-region of RNA and stabilize or destabilize mRNA. Stabilized mRNA undergoes translation in ribosomes, whereas destabilized mRNA undergoes deadenylation, decapping, and degradation in exosomes or P-bodies. (Adapted from reference 130 with permission from the American Society for Clinical Investigation.) (B) Processing of mRNA-encoding PTH. Murine mRNA-encoding PTH is bound by ARE-BPs, which either stabilize or destabilize the mRNA. The ratio of activities of stabilizing/destabilizing ARE-binding proteins bound to mRNA-encoding PTH determines the half-life of the mRNA. KSRP is a mRNA-destabilizing ARE-BP for mRNA-encoding PTH that is active in its dephosphorylated state. The peptidyl-prolyl isomerase Pin1 is responsible for the dephosphorylation of KSRP. In CKD, Pin1 activity is reduced, and as a result less dephosphorylated (active) KSRP is available. Consequently, a stabilizing ARE-BP, AUF1, is active and mRNA-encoding PTH is degraded to a lesser extent, resulting in higher intracellular mRNA levels, more PTH synthesis, and secondary hyperparathyroidism. Abbreviation: P, phosphate. (Adapted from reference 130 with permission from the American Society for Clinical Investigation.)

a low Ca2⫹ diet or by inducing CKD with adenine reduces Pin1 activity in the parathyroid gland.30 Reduced Pin1 activity correlates with increased levels of mRNA-encoding PTH in the PT glands of rats fed a low Ca diet or rats with renal failure. As a result of low 220

Pin1 activity, less nonphosphorylated KSRP is available to bind to the ARE in the 3⬘-UTR of mRNA-encoding PTH.30 The reduction in Pin1 activity reduces the ratio of the ARE-BPs, KSRP, and AUF1. AUF1 activity predominates, and the half-life and stabil-

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ity of mRNA-encoding PTH is increased because of unopposed AUF1 activity. Increased amounts of mRNA allow more PTH to be synthesized in ribosomes and hyperparathyroidism results. It is not known what triggers the reduction in Pin1 activity in the J Am Soc Nephrol 22: 216 –224, 2011

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Parathyroid chief cell Systemic factors

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Figure 5. Alterations within the parathyroid gland that favor the development of 2°HPT in the context of CRF and ESRD.

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parathyroids in CKD and Ca2⫹ deficiency.

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CONCLUSIONS

Thus, in CKD and ESRD, multiple abnormalities contribute to the development of 2°HPT by enhancing the rate of PTH release and synthesis (Figure 5). These factors include a reduction in number of CaSRs in the parathyroid gland, and a reduction in the number of VDRs, which influence the transcription of CaSR and PTH. In addition, there are changes in the amounts of mRNAencoding PTH binding proteins, specifically those that increase mRNA degradation and that favor an increase in levels of mRNA-encoding PTH within the chief cell. Modulators of CaSR and VDR already are available and are in widespread use for the treatment of 2°HPT in CKD and ESRD. The development of parathyroid gland specific modulators of ARE-binding proteins might result in drugs that are effective J Am Soc Nephrol 22: 216 –224, 2011

for the control of secondary hyperparathyroidism and parathyroid hyperplasia. Such drugs might be used in conjunction with vitamin D analogs and calcimimetic agents for the treatment of 2°HPT.

13.

Disclosures

Dr. Kumar’s laboratory is supported by NIH grants DK76829 and DK77669, and grants from Genzyme (GRIP) and Abbott.

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DISCLOSURES None.

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REFERENCES 16. 1. Habener JF, Rosenblatt M, Potts JT Jr.: Parathyroid hormone: Biochemical aspects of biosynthesis, secretion, action, and metabolism. Physiol Rev 64: 985–1053, 1984 2. Potts JT: Parathyroid hormone: Past and present. J Endocrinol 187: 311–325, 2005 3. Kumar R: Metabolism of 1,25-dihydroxyvitamin D3. Physiol Rev 64: 478 –504, 1984 4. DeLuca HF, Schnoes HK: Vitamin D: Recent

17.

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advances. Annu Rev Biochem 52: 411– 439, 1983 Gesek FA, Friedman PA: On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells. J Clin Invest 90: 749 –758, 1992 Isakova T, Gutierrez O, Shah A, Castaldo L, Holmes J, Lee H, Wolf M: Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol 19: 615– 623, 2008 Moranne O, Froissart M, Rossert J, Gauci C, Boffa JJ, Haymann JP, M’Rad MB, Jacquot C, Houillier P, Stengel B, Fouqueray B: Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol 20: 164 –171, 2009 Potts JT, Reita RE, Deftos LJ, Kaye MB, Richardson JA, Buckle RM, Aurbach GD: Secondary hyperparathyroidism in chronic renal disease. Arch Intern Med 124: 408 – 412, 1969 Johnson WJ, Goldsmith RS, Arnaud CD: Prevention and treatment of progressive secondary hyperparathyroidism in advanced renal failure. Med Clin North Am 56: 961–975, 1972 Kumar R: Renal osteodystrophy: A complex disorder. J Lab Clin Med 93: 895– 898, 1979 Bricker NS, Slatopolsky E, Reiss E, Avioli LV: Caclium, phosphorus, and bone in renal disease and transplantation. Arch Intern Med 123: 543–553, 1969 Reiss E, Canterbury JM, Kanter A: Circulating parathyroid hormone concentration in chronic renal insufficiency. Arch Intern Med 124: 417– 422, 1969 Danese MD, Kim J, Doan QV, Dylan M, Griffiths R, Chertow GM: PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis. Am J Kidney Dis 47: 149 –156, 2006 Jadoul M, Albert JM, Akiba T, Akizawa T, Arab L, Bragg-Gresham JL, Mason N, Prutz KG, Young EW, Pisoni RL: Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int 70: 1358 –1366, 2006 Rudser KD, de Boer IH, Dooley A, Young B, Kestenbaum B: Fracture risk after parathyroidectomy among chronic hemodialysis patients. J Am Soc Nephrol 18: 2401–2407, 2007 Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM: Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15: 2208 –2218, 2004 Slatopolsky E, Bricker NS: The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 4: 141–145, 1973 Slatopolsky E, Caglar S, Gradowska L, Can-

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222

www.jasn.org

terbury J, Reiss E, Bricker NS: On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake. Kidney Int 2: 147–151, 1972 Slatopolsky E, Caglar S, Pennell JP, Taggart DD, Canterbury JM, Reiss E, Bricker NS: On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 50: 492– 499, 1971 Slatopolsky E, Gradowska L, Kashemsant C, Keltner R, Manley C, Bricker NS: The control of phosphate excretion in uremia. J Clin Invest 45: 672– 677, 1966 McCarthy JT, Kumar R: Behavior of the vitamin D endocrine system in the development of renal osteodystrophy. Semin Nephrol 6: 21–30, 1986 McCarthy JT, Kumar R: Renal osteodystrophy. Endocrinol Metab Clin North Am 19: 65–93, 1990 Brown AJ, Dusso A, Lopez-Hilker S, LewisFinch J, Grooms P, Slatopolsky E: 1,25(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs. Kidney Int 35: 19 –23, 1989 Brown AJ, Zhong M, Finch J, Ritter C, McCracken R, Morrissey J, Slatopolsky E: Rat calcium-sensing receptor is regulated by vitamin D but not by calcium. Am J Physiol 270: F454 –F460, 1996 Ritter CS, Finch JL, Slatopolsky EA, Brown AJ: Parathyroid hyperplasia in uremic rats precedes down-regulation of the calcium receptor. Kidney Int 60: 1737–1744, 2001 Ritter CS, Martin DR, Lu Y, Slatopolsky E, Brown AJ: Reversal of secondary hyperparathyroidism by phosphate restriction restores parathyroid calcium-sensing receptor expression and function. J Bone Miner Res 17: 2206 –2213, 2002 Naveh-Many T, Bell O, Silver J, Kilav R: Cis and trans acting factors in the regulation of parathyroid hormone (PTH) mRNA stability by calcium and phosphate. FEBS Lett 529: 60 – 64, 2002 Naveh-Many T, Sela-Brown A, Silver J: Protein-RNA interactions in the regulation of PTH gene expression by calcium and phosphate. Nephrol Dial Transplant 14: 811– 813, 1999 Nechama M, Ben-Dov IZ, Briata P, Gherzi R, Naveh-Many T: The mRNA decay promoting factor K-homology splicing regulator protein post-transcriptionally determines parathyroid hormone mRNA levels. Faseb J 22: 3458 –3468, 2008 Nechama M, Uchida T, Mor Yosef-Levi I, Silver J, Naveh-Many T: The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism. J Clin Invest 119: 3102–3114, 2009 Dusso AS, Arcidiacono MV, Sato T, Alvarez-Hernandez D, Yang J, Gonzalez-Su-

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

arez I, Tominaga Y, Slatopolsky E: Molecular basis of parathyroid hyperplasia. J Ren Nutr 17: 45– 47, 2007 Dusso AS, Sato T, Arcidiacono MV, AlvarezHernandez D, Yang J, Gonzalez-Suarez I, Tominaga Y, Slatopolsky E: Pathogenic mechanisms for parathyroid hyperplasia. Kidney Int Suppl S8–S11, 2006 Locatelli F, Cannata-Andia JB, Drueke TB, Horl WH, Fouque D, Heimburger O, Ritz E: Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant 17: 723–731, 2002 Moe SM, Drueke TB: Management of secondary hyperparathyroidism: The importance and the challenge of controlling parathyroid hormone levels without elevating calcium, phosphorus, and calciumphosphorus product. Am J Nephrol 23: 369 –379, 2003 Block GA, Martin KJ, de Francisco AL, Turner SA, Avram MM, Suranyi MG, Hercz G, Cunningham J, Abu-Alfa AK, Messa P, Coyne DW, Locatelli F, Cohen RM, Evenepoel P, Moe SM, Fournier A, Braun J, McCary LC, Zani VJ, Olson KA, Drueke TB, Goodman WG: Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350: 1516 – 1525, 2004 Shoben AB, Rudser KD, de Boer IH, Young B, Kestenbaum B: Association of oral calcitriol with improved survival in nondialyzed CKD. J Am Soc Nephrol 19: 1613– 1619, 2008 Fox J, Heath H 3rd: The “calcium clamp”: Effect of constant hypocalcemia on parathyroid hormone secretion. Am J Physiol 240: E649 –E655, 1981 Cantley LK, Russell J, Lettieri D, Sherwood LM: 1,25-Dihydroxyvitamin D3 suppresses parathyroid hormone secretion from bovine parathyroid cells in tissue culture. Endocrinology 117: 2114 –2119, 1985 Russell J, Lettieri D, Sherwood LM: Suppression by 1,25(OH)2D3 of transcription of the pre-proparathyroid hormone gene. Endocrinology 119: 2864 –2866, 1986 Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM: Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 78: 1296 –1301, 1986 Silver J, Russell J, Sherwood LM: Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A 82: 4270 – 4273, 1985 Hofer AM, Brown EM: Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol 4: 530 –538, 2003 Potts JT, Gardella TJ: Progress, paradox, and potential: Parathyroid hormone re-

Journal of the American Society of Nephrology

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

search over five decades. Ann N Y Acad Sci 1117: 196 –208, 2007 Moallem E, Kilav R, Silver J, Naveh-Many T: RNA-Protein binding and post-transcriptional regulation of parathyroid hormone gene expression by calcium and phosphate. J Biol Chem 273: 5253–5259, 1998 Russell J, Bar A, Sherwood LM, Hurwitz S: Interaction between calcium and 1,25-dihydroxyvitamin D3 in the regulation of preproparathyroid hormone and vitamin D receptor messenger ribonucleic acid in avian parathyroids. Endocrinology 132: 2639 –2644, 1993 Naveh-Many T, Friedlaender MM, Mayer H, Silver J: Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat. Dominant role of 1,25-dihydroxyvitamin D. Endocrinology 125: 275–280, 1989 Naveh-Many T, Silver J: Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat. J Clin Invest 86: 1313–1319, 1990 Hawa NS, O’Riordan JL, Farrow SM: Posttranscriptional regulation of bovine parathyroid hormone synthesis. J Mol Endocrinol 10: 43– 49, 1993 Vadher S, Hawa NS, O’Riordan JL, Farrow SM: Translational regulation of parathyroid hormone gene expression and RNA: Protein interactions. J Bone Miner Res 11: 746 –753, 1996 Habener JF, Kemper B, Potts JT Jr.: Calcium-dependent intracellular degradation of parathyroid hormone: A possible mechanism for the regulation of hormone stores. Endocrinology 97: 431– 441, 1975 Morrissey JJ, Cohn DV: Secretion and degradation of parathormone as a function of intracellular maturation of hormone pools. Modulation by calcium and dibutyryl cyclic AMP. J Cell Biol 83: 521–528, 1979 Roth SI, Raisz LG: Effect of calcium concentration on the ultrastructure of rat parathyroid in organ culture. Lab Invest 13: 331– 345, 1964 Bai M, Quinn S, Trivedi S, Kifor O, Pearce SH, Pollak MR, Krapcho K, Hebert SC, Brown EM: Expression and characterization of inactivating and activating mutations in the human Ca2⫹o-sensing receptor. J Biol Chem 271: 19537–19545, 1996 Rogers KV, Dunn CK, Conklin RL, Hadfield S, Petty BA, Brown EM, Hebert SC, Nemeth EF, Fox J: Calcium receptor messenger ribonucleic acid levels in the parathyroid glands and kidney of vitamin D-deficient rats are not regulated by plasma calcium or 1,25-dihydroxyvitamin D3. Endocrinology 136: 499 –504, 1995 Canaff L, Hendy GN: Human calciumsensing receptor gene. Vitamin D response elements in promoters P1 and P2

J Am Soc Nephrol 22: 216 –224, 2011

www.jasn.org

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66. 67.

68.

69.

confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem 277: 30337–30350, 2002 Yao JJ, Bai S, Karnauskas AJ, Bushinsky DA, Favus MJ: Regulation of renal calcium receptor gene expression by 1,25-dihydroxyvitamin D3 in genetic hypercalciuric stone-forming rats. J Am Soc Nephrol 16: 1300 –1308, 2005 Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC: Cloning and characterization of an extracellular Ca(2⫹)-sensing receptor from bovine parathyroid. Nature 366: 575–580, 1993 Brown EM, Hebert SC: Calcium-receptorregulated parathyroid and renal function. Bone 20: 303–309, 1997 Brown EM, MacLeod RJ: Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 81: 239 –297, 2001 Brown EM, Pollak M, Hebert SC: Molecular mechanisms underlying the sensing of extracellular Ca2⫹ by parathyroid and kidney cells. Eur J Endocrinol 132: 523–531, 1995 Brown EM, Pollak M, Hebert SC: The extracellular calcium-sensing receptor: Its role in health and disease. Annu Rev Med 49: 15– 29, 1998 Brown EM, Pollak M, Riccardi D, Hebert SC: Cloning and characterization of an extracellular Ca(2⫹)-sensing receptor from parathyroid and kidney: New insights into the physiology and pathophysiology of calcium metabolism. Nephrol Dial Transplant 9: 1703–1706, 1994 Schwarz P, Larsen NE, Lonborg Friis IM, Lillquist K, Brown EM, Gammeltoft S: Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism associated with mutations in the human Ca2⫹-sensing receptor gene in three Danish families. Scand J Clin Lab Invest 60: 221–227, 2000 Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG: Mutations in the human Ca(2⫹)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75: 1297–1303, 1993 Brown EM, Pollak M, Hebert SC: Sensing of extracellular Ca2⫹ by parathyroid and kidney cells: Cloning and characterization of an extracellular Ca(2⫹)-sensing receptor. Am J Kidney Dis 25: 506 –513, 1995 Hebert SC: Bartter syndrome. Curr Opin Nephrol Hypertens 12: 527–532, 2003 Brown EM: Mutations in the calcium-sensing receptor and their clinical implications. Horm Res 48: 199 –208, 1997 Chattopadhyay N, Mithal A, Brown EM: The calcium-sensing receptor: A window into the physiology and pathophysiology of mineral ion metabolism. Endocr Rev 17: 289 –307, 1996 Bai M, Trivedi S, Brown EM: Dimerization

J Am Soc Nephrol 22: 216 –224, 2011

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaRtransfected HEK293 cells. J Biol Chem 273: 23605–23610, 1998 Bai M, Trivedi S, Kifor O, Quinn SJ, Brown EM: Intermolecular interactions between dimeric calcium-sensing receptor monomers are important for its normal function. Proc Natl Acad Sci U S A 96: 2834 –2839, 1999 Fan GF, Ray K, Zhao XM, Goldsmith PK, Spiegel AM: Mutational analysis of the cysteines in the extracellular domain of the human Ca2⫹ receptor: Effects on cell surface expression, dimerization and signal transduction. FEBS Lett 436: 353–356, 1998 Ward DT, Brown EM, Harris HW: Disulfide bonds in the extracellular calcium-polyvalent cation-sensing receptor correlate with dimer formation and its response to divalent cations in vitro. J Biol Chem 273: 14476 –14483, 1998 Zhang Z, Sun S, Quinn SJ, Brown EM, Bai M: The extracellular calcium-sensing receptor dimerizes through multiple types of intermolecular interactions. J Biol Chem 276: 5316 –5322, 2001 Guex N, Peitsch MC: SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis 18: 2714 –2723, 1997 Kelley LA, MacCallum RM, Sternberg MJ: Enhanced genome annotation using structural profiles in the program 3D-PSSM. J Mol Biol 299: 499 –520, 2000 Kopp J, Schwede T: The SWISS-MODEL Repository of annotated three-dimensional protein structure homology models. Nucleic Acids Res 32: D230 –D234, 2004 Schwede T, Kopp J, Guex N, Peitsch MC: SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res 31: 3381–3385, 2003 Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, Nakanishi S, Jingami H, Morikawa K: Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407: 971–977, 2000 Tsuchiya D, Kunishima N, Kamiya N, Jingami H, Morikawa K: Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3⫹. Proc Natl Acad Sci U S A 99: 2660 –2665, 2002 Nemeth EF, Bennett SA: Tricking the parathyroid gland with novel calcimimetic agents. Nephrol Dial Transplant 13: 1923– 1925, 1998 Nemeth EF: Calcimimetic and calcilytic drugs: Just for parathyroid cells? Cell Calcium 35: 283–289, 2004 Nemeth EF: Pharmacological regulation of

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

BRIEF REVIEW

parathyroid hormone secretion. Curr Pharm Des 8: 2077–2087, 2002 Mun HC, Franks AH, Culverston E, Krapcho K, Nemeth EF, Conigrave AD: The Venus Fly Trap domain of the extracellular Ca2⫹sensing receptor is required for L-amino acid sensing. J Biol Chem 279: 51739 – 51744, 2004 Brown EM, Butters R, Katz C, Kifor O: Neomycin mimics the effects of high extracellular calcium concentrations on parathyroid function in dispersed bovine parathyroid cells. Endocrinology 128: 3047–3054, 1991 Brown EM, Vassilev PM, Quinn S, Hebert SC: G-protein-coupled, extracellular Ca(2⫹)sensing receptor: A versatile regulator of diverse cellular functions. Vitam Horm 55: 1–71, 1999 Fox J, Lowe SH, Conklin RL, Petty BA, Nemeth EF: Calcimimetic compound NPS R-568 stimulates calcitonin secretion but selectively targets parathyroid gland Ca(2⫹) receptor in rats. J Pharmacol Exp Ther 290: 480–486, 1999 Nemeth EF, Delmar EG, Heaton WL, Miller MA, Lambert LD, Conklin RL, Gowen M, Gleason JG, Bhatnagar PK, Fox J: Calcilytic compounds: Potent and selective Ca2⫹ receptor antagonists that stimulate secretion of parathyroid hormone. J Pharmacol Exp Ther 299: 323–331, 2001 Nemeth EF, Fox J: Calcimimetic compounds: A direct approach to controlling plasma levels of parathyroid hormone in hyperparathyroidism. Trends Endocrinol Metab 10: 66 –71, 1999 Nemeth EF, Steffey ME, Hammerland LG, Hung BC, Van Wagenen BC, DelMar EG, Balandrin MF: Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A 95: 4040 – 4045, 1998 Block GA, Zeig S, Sugihara J, Chertow GM, Chi EM, Turner SA, Bushinsky DA: Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism. Nephrol Dial Transplant 23: 2311–2318, 2008 Silverberg SJ, Bilezikian JP: The diagnosis and management of asymptomatic primary hyperparathyroidism. Nat Clin Pract Endocrinol Metab 2: 494 –503, 2006 Valle C, Rodriguez M, Santamaria R, Almaden Y, Rodriguez ME, Canadillas S, MartinMalo A, Aljama P: Cinacalcet reduces the set point of the PTH-calcium curve. J Am Soc Nephrol 19: 2430 –2436, 2008 Gowen M, Stroup GB, Dodds RA, James IE, Votta BJ, Smith BR, Bhatnagar PK, Lago AM, Callahan JF, DelMar EG, Miller MA, Nemeth EF, Fox J: Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest 105: 1595–1604, 2000

PTH Secretion and Synthesis

223

BRIEF REVIEW

www.jasn.org

94. Rubin MR, Bilezikian JP: New anabolic therapies in osteoporosis. Endocrinol Metab Clin North Am 32: 285–307, 2003 95. Hieronymus H, Silver PA: A systems view of mRNP biology. Genes Dev 18: 2845–2860, 2004 96. Tfelt-Hansen J, Chattopadhyay N, Yano S, Kanuparthi D, Rooney P, Schwarz P, Brown EM: Calcium-sensing receptor induces proliferation through p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase but not extracellularly regulated kinase in a model of humoral hypercalcemia of malignancy. Endocrinology 145: 1211–1217, 2004 97. Hjalm G, MacLeod RJ, Kifor O, Chattopadhyay N, Brown EM: Filamin-A binds to the carboxyl-terminal tail of the calciumsensing receptor, an interaction that participates in CaR-mediated activation of mitogen-activated protein kinase. J Biol Chem 276: 34880 –34887, 2001 98. Arthur JM, Lawrence MS, Payne CR, Rane MJ, McLeish KR: The calcium-sensing receptor stimulates JNK in MDCK cells. Biochem Biophys Res Commun 275: 538 –541, 2000 99. Hobson SA, Wright J, Lee F, McNeil SE, Bilderback T, Rodland KD: Activation of the MAP kinase cascade by exogenous calcium-sensing receptor. Mol Cell Endocrinol 200: 189 –198, 2003 100. Ye CP, Yano S, Tfelt-Hansen J, MacLeod RJ, Ren X, Terwilliger E, Brown EM, Chattopadhyay N: Regulation of a Ca2⫹-activated K⫹ channel by calcium-sensing receptor involves p38 MAP kinase. J Neurosci Res 75: 491– 498, 2004 101. Huang C, Wu Z, Hujer KM, Miller RT: Silencing of filamin A gene expression inhibits Ca2⫹-sensing receptor signaling. FEBS Lett 580: 1795–1800, 2006 102. Davies SL, Gibbons CE, Vizard T, Ward DT: Ca2⫹-sensing receptor induces Rho kinase-mediated actin stress fiber assembly and altered cell morphology, but not in response to aromatic amino acids. Am J Physiol Cell Physiol 290: C1543–C1551, 2006 103. Rey O, Young SH, Yuan J, Slice L, Rozengurt E: Amino acid-stimulated Ca2⫹ oscillations produced by the Ca2⫹-sensing receptor are mediated by a phospholipase C/inositol 1,4,5-trisphosphate-independent pathway that requires G12, Rho, filamin-A, and the actin cytoskeleton. J Biol Chem 280: 22875–22882, 2005 104. Zhang M, Breitwieser GE: High affinity interaction with filamin A protects against calcium-sensing receptor degradation. J Biol Chem 280: 11140–11146, 2005 105. Loretz CA, Pollina C, Hyodo S, Takei Y, Chang W, Shoback D: cDNA cloning and functional expression of a Ca2⫹-sensing receptor with truncated C-terminal tail from the Mozambique tilapia (Oreochro-

224

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

mis mossambicus). J Biol Chem 279: 53288 –53297, 2004 Ward DT: Calcium receptor-mediated intracellular signalling. Cell Calcium 35: 217–228, 2004 Carfi A, Gong H, Lou H, Willis SH, Cohen GH, Eisenberg RJ, Wiley DC: Crystallization and preliminary diffraction studies of the ectodomain of the envelope glycoprotein D from herpes simplex virus 1 alone and in complex with the ectodomain of the human receptor HveA. Acta Crystallogr D Biol Crystallogr 58: 836 – 838, 2002 Awata H, Huang C, Handlogten ME, Miller RT: Interaction of the calcium-sensing receptor and filamin, a potential scaffolding protein. J Biol Chem 276: 34871–34879, 2001 Brown AJ, Ritter CS, Finch JL, Slatopolsky EA: Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: Role of dietary phosphate. Kidney Int 55: 1284 –1292, 1999 Martin-Salvago M, Villar-Rodriguez JL, Palma-Alvarez A, Beato-Moreno A, GaleraDavidson H: Decreased expression of calcium receptor in parathyroid tissue in patients with hyperparathyroidism secondary to chronic renal failure. Endocr Pathol 14: 61–70, 2003 Mathias RS, Nguyen HT, Zhang MY, Portale AA: Reduced expression of the renal calcium-sensing receptor in rats with experimental chronic renal insufficiency. J Am Soc Nephrol 9: 2067–2074, 1998 Yano S, Sugimoto T, Tsukamoto T, Chihara K, Kobayashi A, Kitazawa S, Maeda S, Kitazawa R: Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 58: 1980 –1986, 2000 Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM: Sequences in the human parathyroid hormone gene that bind the 1,25dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A 89: 8097–8101, 1992 McKee AE, Silver PA: Systems perspectives on mRNA processing. Cell Res 17: 581– 590, 2007 Bentley DL: Rules of engagement: Co-transcriptional recruitment of pre-mRNA processing factors. Curr Opin Cell Biol 17: 251–256, 2005 Blencowe BJ: Alternative splicing: New insights from global analyses. Cell 126: 37– 47, 2006 Kornblihtt AR, de la Mata M, Fededa JP, Munoz MJ, Nogues G: Multiple links between transcription and splicing. RNA 10: 1489 –1498, 2004 Moore MJ: From birth to death: The com-

Journal of the American Society of Nephrology

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

plex lives of eukaryotic mRNAs. Science 309: 1514 –1518, 2005 Sanchez-Diaz P, Penalva LO: Post-transcription meets post-genomic: The saga of RNA binding proteins in a new era. RNA Biol 3: 101–109, 2006 Singh R, Valcarcel J: Building specificity with nonspecific RNA-binding proteins. Nat Struct Mol Biol 12: 645– 653, 2005 Barreau C, Paillard L, Osborne HB: AU-rich elements and associated factors: Are there unifying principles? Nucleic Acids Res 33: 7138 –7150, 2005 Misquitta CM, Chen T, Grover AK: Control of protein expression through mRNA stability in calcium signalling. Cell Calcium 40: 329 –346, 2006 Schiavi SC, Belasco JG, Greenberg ME: Regulation of proto-oncogene mRNA stability. Biochim Biophys Acta 1114: 95– 106, 1992 Schiavi SC, Wellington CL, Shyu AB, Chen CY, Greenberg ME, Belasco JG: Multiple elements in the c-fos protein-coding region facilitate mRNA deadenylation and decay by a mechanism coupled to translation. J Biol Chem 269: 3441–3448, 1994 Chen CY, Shyu AB: AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci 20: 465–470, 1995 Lebreton A, Tomecki R, Dziembowski A, Seraphin B: Endonucleolytic RNA cleavage by a eukaryotic exosome. Nature 456: 993– 996, 2008 McPheeters DS, Cremona N, Sunder S, Chen HM, Averbeck N, Leatherwood J, Wise JA: A complex gene regulatory mechanism that operates at the nexus of multiple RNA processing decisions. Nat Struct Mol Biol 16: 255–264, 2009 Schilders G, Pruijn GJ: Biochemical studies of the mammalian exosome with intact cells. Methods Enzymol 448: 211– 226, 2008 Kilav R, Bell O, Le SY, Silver J, Naveh-Many T: The parathyroid hormone mRNA 3⬘-untranslated region AU-rich element is an unstructured functional element. J Biol Chem 279: 2109 –2116, 2004 Kumar R: Pin1 regulates parathyroid hormone mRNA stability. J Clin Invest 119: 2887–2891, 2009 Shen ZJ, Esnault S, Malter JS: The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nat Immunol 6: 1280 –1287, 2005 Shen ZJ, Esnault S, Rosenthal LA, Szakaly RJ, Sorkness RL, Westmark PR, Sandor M, Malter JS: Pin1 regulates TGF-beta1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J Clin Invest 118: 479 – 490, 2008

J Am Soc Nephrol 22: 216 –224, 2011