BRIEF REVIEW www.jasn.org 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 basis of these observations regarding failure and sometimes after renal transplantation. Understanding the mechanisms by pathogenesis, therapy for 2°HPT in the which parathyroid hormone (PTH) synthesis and secretion are normally regulated is context of CKD and ESRD includes the important in devising methods to regulate overactivity and hyperplasia of the para- control of serum phosphate concentra- ϩ thyroid gland after the onset of renal insufficiency. Rapid regulation of PTH secretion tions, the administration of Ca2 and in response to variations in serum calcium is mediated by G-protein coupled, calcium- vitamin D analogs, and the administra- sensing receptors on parathyroid cells, whereas alterations in the stability of mRNA- tion of calcimimetics.33,34,16,35,36 encoding PTH by mRNA-binding proteins occur in response to prolonged changes in Nevertheless, 2°HPT remains a signifi- serum calcium. Independent of changes in intestinal calcium absorption and serum cant clinical problem and additional meth- calcium, 1␣,25-dihydroxyvitamin D also represses the transcription of PTH by associ- ods for the treatment of this condition would ating with the vitamin D receptor, which heterodimerizes with retinoic acid X receptors be helpful, especially in refractory situations, to bind vitamin D-response elements within the PTH gene. 1␣,25-Dihydroxyvitamin D where other measures have failed or are only additionally regulates the expression of calcium-sensing receptors to indirectly alter partially effective. Knowledge about the mec- PTH secretion. In 2°HPT seen in renal failure, reduced concentrations of calcium- hanisms by which parathyroid hormone se- sensing and vitamin D receptors, and altered mRNA-binding protein activities within cretion and synthesis occur is therefore of the parathyroid cell, increase PTH secretion in addition to the more widely recognized value in designing new approaches to the changes in serum calcium, phosphorus, and 1␣,25-dihydroxyvitamin D. The treatment treatment of this condition. Here we briefly of secondary hyperparathyroidism by correction of serum calcium and phosphorus review the mechanisms that modulate PTH concentrations and the administration of vitamin D analogs and calcimimetic agents release and secretion and identify abnormal- may be augmented in the future by agents that alter the stability of mRNA-encoding ities that are present in progressive renal dis- PTH. ease. J Am Soc Nephrol 22: ●●●–●●●, 2011. doi: 10.1681/ASN.2010020186 PTH RELEASE AND SYNTHESIS DETERMINE SERUM PTH The central role of the parathyroid creased incidence of fractures and mor- CONCENTRATIONS ϩ glands in regulating Ca2 homeostasis tality.13–16 by modulating bone metabolism, the The pathogenesis of 2°HPT in CKD is Serum PTH concentrations are depen- synthesis of 1␣,25-dihydroxyvitamin complex. Phosphate retention, hyperphos- dent upon the release of PTH stored in ␣ 2ϩ 2ϩ D(1 ,25(OH)2D) in proximal tubules, phatemia, low serum Ca (sCa ), elevated 2ϩ and the reabsorption of Ca in the levels of parathyroid hormone (PTH), Published online ahead of print. Publication date ␣ 2ϩ distal nephron is widely appreciated by 1 ,25(OH)2D deficiency, intestinal Ca available at www.jasn.org. 1–5 the readers of this journal. Second- malabsorption, the reduction of vitamin D Correspondence: Dr. Rajiv Kumar, Division of Ne- ary hyperparathyroidism (2°HPT) fre- receptors (VDR) and calcium-sensing recep- phrology and Hypertension, Departments of Medi- quently occurs in the setting of chronic tors (CaSR) in the parathyroid glands, and cine, Biochemistry and Molecular Biology, Mayo Clinic and Foundation, 200 1st Street SW, Roches- kidney disease (CKD), of end-stage re- altered mRNA-binding protein activities ter, MN 55905. Phone: 507-284-0020; Fax: 507-538- nal disease (ESRD), or after renal trans- modulating PTH transcripts play a role in the 9536; E-mail: [email protected] 6–12 17–30 plantation, and uncontrolled 2°HPT development of 2°HPT. Parathyroid hy- Copyright © ●●●● by the American Society of in CKD and ESRD associates with an in- perplasia is often present as well.31,32 On the Nephrology J Am Soc Nephrol 22: ●●●–●●●, 2011 ISSN : 1046-6673/2202-●●● 1 BRIEF REVIEW www.jasn.org secretory granules within the parathy- roid gland and by the synthesis of new ϩ PTH.1,37 sCa2 , phosphorus, and vita- min D metabolites play a role in regulat- ing PTH release and synthesis.1,3,28,38–41 Rapid PTH release from secretory granules in hypocalcemic states is modulated by the binding of Ca2ϩ to CaSRs on chief cells, Figure 1. A hypothetical dimeric model of residues D23 (blue) to I528 (red) of the human whereas long-term replenishment of PTH calcium sensing receptor extracellular domain (CaSR ECD). (A) Both monomers contain- stores is dependent on new PTH synthesis ing just the Venus flytrap region of the CaSR ECD are shown in a closed and presumably that is controlled by the availability of active conformation as was reported for the extracellular domain of the glutamate mRNA-encoding PTH for ribosomal trans- receptor with glutamate bound. The two yellow spheres (yellow arrows) indicate putative ϩ lation into prepro-PTH.2,42,43,27,44–49 Hy- Ca2 -binding sites, found at the nexus of where both lobes of a monomer meet. Most pocalcemia also retards the rate of degrada- residues forming this cation-binding site are not conserved in glutamate receptor. The tion of PTH within the parathyroid gland, additional cyan spheres within the topmost lobes of the dimer designate possible 2ϩ thus making more PTH available for re- Mg -binding sites (green spheres indicated by green arrows) brought over from gluta- 2ϩ lease,50,51 and increases cell division in the mate receptor coordinates. These Mg sites are completely conserved in CaSR. The parathyroid gland possibly through the ac- 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 tion of the CaSR.1,42,45,52 Phosphorus addi- dimer together within this portion of the ECD of CaSR, although two intramolecular tionally alters PTH synthesis, although the disulfides exist. (B) A model of the apo-CaSR dimer is portrayed. Again, the color ramps ϩ precise mechanisms by which changes in from blue to red from D23 to I528. The Mg2 sites are present, although there is no phosphate concentrations are detected experimental basis for this premise. Of note is the significant opening and expansion or sensed by the parathyroid gland are of the cavities between the upper and lower lobes of each monomer, the areas unknown.28 1␣,25-Dihydroxyvitamin indicated by the two yellow ovals. (C) The upper lobes of the CaSR atomic coordi- ␣ 2ϩ D(1 ,25(OH)2D) alters the transcrip- nates shown above in (A) (with Ca bound, now made gray in color) are superim- tion of PTH and may have an indirect posed on the apo-form model for the CaSR dimer drawn in rainbow as in (B). The red effect on PTH release by increasing the arrows point to a large displacement in the orientation and position of the carboxy- expression of CaSR.38–41,45,53–56 terminal 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. ROLE OF THE CASR IN MEDIATING PTH RELEASE meostasis is demonstrated by the bio- 1ewk)78 as the template for main chain logic consequences of inactivating or atoms. The atomic coordinates within Changes in concentrations of sCa2ϩ are activating mutations of the receptor. the model were inspected and manually sensed by chief cells through a cell-sur- Inactivating mutations of the CaSR result corrected for steric clashes, for alterna- face, seven-transmembrane, G protein– in familial benign hypercalcemia or neona- tive residue rotamer choices that im- coupled receptor, the CaSR,42,57–59 and tal severe hyperparathyroidism, whereas prove hydrogen bonding, and for Ram- receptor activity results in rapid alter- activating mutations result in autosomal achandran and other conformational ations in PTH secretion.37 After the in- dominant hypocalcemia.62,63,53,64–68 outliers. The CaSR dimer from D23 to duction of abrupt and sustained hy- The CaSR has a large extracellular do- I528 displays perfect twofold symmetry pocalcemia, plasma concentrations of main of approximately 600 amino acids, similar to that of the glutamate receptor PTH increase within 1 minute, peak at 4 a seven-pass transmembrane domain, bound with both glutamate and gadolin- ϩ to 10 minutes, and thereafter decline and an intracellular carboxyl-terminal ium ions.79 The putative Ca2 -binding gradually to approximately 60% of the domain that has several phosphorylation sites were included in our CaSR model ϩ ϩ maximum at 60 minutes, despite ongo- sites.69 The receptor binds Ca2 in its ex- based on the presence of Gd2 atomic ing and constant hypocalcemia. Abrupt tracellular domain, most likely as a dimer coordinates within other glutamate re- restoration of normocalcemia from the in the so-called “Venus flytrap” configu- ceptor structures (PDBs 1ewk and 1isr). ϩ hypocalcemic state causes levels of PTH ration (Figure 1, A through C).70–73 Our In the glutamate receptor, the Gd2 lo- to decrease with an apparent half-life of model of the human CaSR shown in Fig- cation occurs at an acidic patch, includ- approximately 3 minutes. In addition to ure 1 was obtained using multiple se- ing the ligating residues E238, D215, and its role in the parathyroid gland, the quence alignments and initial coordinate E224 with one standout residue R220.