Parathyroid hormone

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Parathyroid hormone
Protein PTH PDB 1bwx.png
PDB rendering based on 1bwx.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PTH ; PTH1
External IDs OMIM168450 MGI97799 HomoloGene266 GeneCards: PTH Gene
RNA expression pattern
PBB GE PTH 206977 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5741 19226
Ensembl ENSG00000152266 ENSMUSG00000059077
UniProt P01270 n/a
RefSeq (mRNA) NM_000315 NM_020623
RefSeq (protein) NP_000306 NP_065648
Location (UCSC) Chr 11:
13.49 – 13.5 Mb
Chr 7:
113.39 – 113.39 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, yet effective hormone-receptor interaction requires solely the 34-N-terminal amino acids. While PTH acts to increase the concentration of ionic calcium (Ca2+) in the blood, calcitonin, a hormone produced by the parafollicular cells (C cells) of the thyroid gland, acts to decrease ionic calcium concentration. PTH essentially acts to increase the concentration of calcium in the blood by acting upon the parathyroid hormone 1 receptor, which is present at high levels in bone and kidney, and the parathyroid hormone 2 receptor, which is present at 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 approximately 9.4 kDa.[3]

Structure[edit]

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.

helical dimer structure of hPTH-(1-34)[5]

Function[edit]

Regulation of serum calcium[edit]

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 available for binding the excess RANKL) 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.
Calcium regulation in the human body.[9] The role of parathyroid hormone is shown in blue.

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[edit]

PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney,[11] 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[edit]

PTH increases the activity of 1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of vitamin D, in the kidney.

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway edit]]
Vitamin D Synthesis Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531". 

Regulation of PTH secretion[edit]

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 elevated. The G-protein coupled calcium receptors bind extracellular calcium and may be found on the surface on a wide variety of cells distributed in the brain, heart, skin, stomach, C cells, and other tissues. In the parathyroid gland, 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. A mild decrease in serum magnesium levels stimulates the resorptive activity PTH has on the kidneys. Severe Hypomagnesemia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.[12]

Stimulators[edit]

  • Decreased serum [Ca2+].
  • Mild decreases in serum [Mg2+].
  • An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH).

Inhibitors[edit]

Clinical significance[edit]

  • Hyperparathyroidism, the presence of excessive amounts of parathyroid hormone in the blood, occurs in two very distinct sets of circumstances. Primary hyperparathyroidism is due to autonomous, abnormal hypersecretion of PTH from the parathyroid gland, while secondary hyperparathyroidism is an appropriately high PTH level seen as a physiological response to hypocalcaemia.
  • A low level of PTH in the blood is known as hypoparathyroidism and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.
  • In osteoporotic women, administration of an exogenous parathyroid hormone analogue (teriparatide, by daily injection) superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45 to 65%.[14]

Measurement[edit]

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 8–51 pg/ml.[15]

Model organisms[edit]

Model organisms have been used in the study of PTH function. A conditional knockout mouse line called Pthtm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[16] Male and female animals underwent a standardized phenotypic screen[17] to determine the effects of deletion.[18][19][20][21] Additional screens performed: - In-depth immunological phenotyping[22]



See also[edit]

References[edit]

  1. ^ Physiology: 5/5ch6/s5ch6_11 - Essentials of Human Physiology
  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. 
  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". Nature Structural & Molecular Biology 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. 
  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. ^ 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. p. 1300. ISBN 1-4160-2328-3. 
  10. ^ Zieve, MD, MHA, David. "MedlinePlus Medical Encyclopedia: Serum calcium". National Library of Medicine, National Institutes of Health. Retrieved 2009-02-01. 
  11. ^ Gardner, David; Shoback, Dolores (2011). Greenspan's Basic & Clinical Endocrinology (9th ed.). McGraw Hill. p. 232. ISBN 978-0071622431. 
  12. ^ Agus ZS (July 1999). "Hypomagnesemia". J. Am. Soc. Nephrol. 10 (7): 1616–22. PMID 10405219. 
  13. ^ Costanzo, Linda S. (2007). BRS Physiology. Lippincott, Williams, & Wilkins. p. 260. ISBN 978-0-7817-7311-9. 
  14. ^ Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (May 2001). "Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis". N. Engl. J. Med. 344 (19): 1434–41. doi:10.1056/NEJM200105103441904. PMID 11346808. 
  15. ^ Longo et al. Harrison's Principles of Internal Medicine, 18th ed., p.3594
  16. ^ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Opthalmologica 88: 925-7.doi:10.1111/j.1755-3768.2010.4142.x: Wiley. 
  17. ^ a b "International Mouse Phenotyping Consortium". 
  18. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V et al. (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750. 
  19. ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718. 
  20. ^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  21. ^ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN et al. (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMID 23870131. 
  22. ^ a b "Infection and Immunity Immunophenotyping (3i) Consortium". 

Further reading[edit]

External links[edit]