Parathyroid hormone

Parathyroid hormone

PDB rendering based on 1bwx.
Identifiers
Symbols PTH;
External IDs OMIM: 168450 MGI: 97799 HomoloGene: 266 GeneCards: PTH Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 5741 19226
Ensembl ENSG00000152266 ENSMUSG00000059077
UniProt P01270 n/a
RefSeq (mRNA) NM_000315.2 NM_020623.2
RefSeq (protein) NP_000306.1 NP_065648.1
Location (UCSC) Chr 11:
13.51 – 13.52 Mb		 Chr 7:
120.53 – 120.53 Mb
PubMed search [1] [2]

Parathyroid hormone (PTH), parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids. It acts to increase the concentration of calcium (Ca2+) in the blood, whereas calcitonin (a hormone produced by the parafollicular cells (C cells) of the thyroid gland) acts to decrease calcium concentration. PTH acts to increase the concentration of calcium in the blood by acting upon the parathyroid hormone 1 receptor (high levels in bone and kidney) and the parathyroid hormone 2 receptor (high levels in the central nervous system, pancreas, testis, and placenta).[1] PTH half-life is approximately 4 minutes.[2] It has a molecular mass of 9.4 kDa.[3]

Contents

Structure

hPTH-(1-34) crystallizes as a slightly bent, long helical dimer. Analysis reveals that the extended helical conformation of hPTH-(1-34) is the likely bioactive conformation.[4] The N-terminal fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9 Å resolution.

Function

Regulation of serum calcium

Parathyroid hormone regulates serum calcium through its effects on the following tissues:[6]

Region Effect
bone It enhances the release of calcium from the large reservoir contained in the bones.[7] Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their expression of Osteoprotegerin(OPG). OPG binds to RANKL and blocks it from interacting with RANK, a receptor for RANKL. The binding of RANKL to RANK (facilitated by the decreased amount of OPG) stimulates these osteoclast precursors to fuse, forming new osteoclasts, which ultimately enhances bone resorption.
kidney It enhances active reabsorption of calcium and magnesium from distal tubules and the thick ascending limb. As bone is degraded, both calcium and phosphate are released. It also decreases the reabsorption of phosphate, with a net loss in plasma phosphate concentration. When the calcium:phosphate ratio increases, more calcium is free in the circulation.[8]
intestine via kidney It enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D activation occurs in the kidney. PTH up-regulates 25-hydroxyvitamin D3 1-alpha-hydroxylase, the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). This activated form of vitamin D increases the absorption of calcium (as Ca2+ ions) by the intestine via calbindin.

PTH was one of the first hormones to be shown to use the G-protein, adenylyl cyclase second messenger system.

Normal total plasma calcium level ranges from 8.5 to 10.2 mg/dL (2.12 mmol/L to 2.55 mmol/L).[10]

Regulation of serum phosphate

PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney,[8] which means more phosphate is excreted through the urine.

However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, absorption of both Calcium and Phosphate is mediated by an increase in activated vitamin D. The absorption of phosphate is not as dependent on vitamin D as is that of calcium. The end result of PTH release is a small net drop in the serum concentration of phosphate.

Vitamin D synthesis

PTH increases the activity of 1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol, the active form of vitamin D.

Regulation of PTH secretion

Secretion of parathyroid hormone is controlled chiefly by serum [Ca2+] through negative feedback. Calcium-sensing receptors located on parathyroid cells are activated when [Ca2+] is low.[11] The G-protein coupled calcium receptors (CaR) sense extracellular calcium and may be found on the surface on a wide variety cells distributed in the brain, heart, skin, stomach, C cells, and other tissues. In the parathyroid gland, sensation of high concentrations of extracellular calcium result in activation of the Gq G-protein coupled cascade through the action of phospholipase C. This hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to liberate intracellular messengers IP3 and diacylglycerol (DAG). Ultimately, these two messengers result in a release of calcium from intracellular stores and a subsequent flux of extracellular calcium into the cytoplasmic space. The effect of this signaling of high extracellular calcium results in an intracellular calcium concentration that inhibits the secretion of preformed PTH from storage granules in the parathyroid gland. In contrast to the mechanism that most secretory cells use, calcium inhibits vesicle fusion and release of PTH. In the parathyroids, magnesium serves this role in stimulus-secretion coupling. Hypomagnesia may result in a paralysis of PTH secretion and lead to a form of hypoparathyroidism that is reversible.

Stimulators

Inhibitors

Clinical significance

Measurement

PTH can be measured in the blood in several different forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH, and different tests are used in different clinical situations.

The average PTH level is 10-60 pg/ml.

See also

References

  1. ^ Physiology at MCG 5/5ch6/s5ch6_11
  2. ^ Bieglmayer C, Prager G, Niederle B (October 2002). "Kinetic analyses of parathyroid hormone clearance as measured by three rapid immunoassays during parathyroidectomy". Clin. Chem. 48 (10): 1731–8. PMID 12324490. http://www.clinchem.org/cgi/content/abstract/48/10/1731. 
  3. ^ Prahalad AK, Hickey RJ, Huang J, et al. (June 2006). "Serum proteome profiles identifies parathyroid hormone physiologic response". Proteomics 6 (12): 3482–93. doi:10.1002/pmic.200500929. PMID 16705755. 
  4. ^ Jin L, Briggs SL, Chandrasekhar S, Chirgadze NY, Clawson DK, Schevitz RW, Smiley DL, Tashjian AH, Zhang F (September 2000). "Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution". J. Biol. Chem. 275 (35): 27238–44. doi:10.1074/jbc.M001134200. PMID 10837469. 
  5. ^ PDB 1ETE; Savvides SN, Boone T, Andrew Karplus P (June 2000). "Flt3 ligand structure and unexpected commonalities of helical bundles and cystine knots". Nat Struct Biol. 7 (6): 486–491. doi:10.1038/75896. PMID 10881197. ; rendered via PyMOL.
  6. ^ Coetzee M, Kruger MC (May 2004). "Osteoprotegerin-receptor activator of nuclear factor-kappaB ligand ratio: a new approach to osteoporosis treatment?". South. Med. J. 97 (5): 506–11. doi:10.1097/00007611-200405000-00018. PMID 15180028. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0038-4348&volume=97&issue=5&spage=506. 
  7. ^ Poole K, Reeve J (2005). "Parathyroid hormone - a bone anabolic and catabolic agent". Curr Opin Pharmacol 5 (6): 612–7. doi:10.1016/j.coph.2005.07.004. PMID 16181808. 
  8. ^ a b http://sprojects.mmi.mcgill.ca/nephrology/presentation/presentation5.htm
  9. ^ Page 1094 (The Parathyroid Glands and Vitamin D) in: Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. pp. 1300. ISBN 1-4160-2328-3. 
  10. ^ Zieve, MD, MHA, David. "MedlinePlus Medical Encyclopedia: Serum calcium". National Library of Medicine, National Institutes of Health. http://www.nlm.nih.gov/medlineplus/ency/article/003477.htm. Retrieved 2009-02-01. 
  11. ^ Physiology at MCG 5/5ch6/s5ch6_9
  12. ^ Costanzo, Linda S. (2007). BRS Physiology. Lippincott, Williams, & Wilkins. pp. 260. ISBN 978-0781773119. http://www.amazon.com/Physiology-Board-Review-Linda-Costanzo/dp/0781773113/. 

Further reading