Parathyroid hormone

Parathyroid hormone (PTH), parathormone or parathyrin, is secreted by the chief cells of the is_associated_with::parathyroid glands as a is_associated_with::polypeptide containing 84 is_associated_with::amino acids, yet effective hormone-receptor interaction requires solely the 34-N-terminal amino acids. While PTH acts to increase the concentration of ionic is_associated_with::calcium (Ca2+) in the is_associated_with::blood, is_associated_with::calcitonin, a hormone produced by the is_associated_with::parafollicular cells (C cells) of the is_associated_with::thyroid gland, acts to decrease ionic calcium concentration. PTH essentially acts to increase the concentration of calcium in the blood by acting upon the is_associated_with::parathyroid hormone 1 receptor, which is present at high levels in bone and kidney, and the is_associated_with::parathyroid hormone 2 receptor, which is present at high levels in the central nervous system, pancreas, testis, and placenta. PTH half-life is approximately 4 minutes. It has a molecular mass of approximately 9.4 kDa.

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. The N-terminal fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9 Å resolution.

Regulation of serum calcium
Parathyroid hormone regulates is_associated_with::serum calcium through its effects on the following tissues:



PTH was one of the first hormones to be shown to use the G-protein, is_associated_with::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).

Regulation of serum phosphate
PTH reduces the reabsorption of is_associated_with::phosphate from the is_associated_with::proximal tubule of the is_associated_with::kidney, 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 is_associated_with::1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of is_associated_with::vitamin D, in the is_associated_with::kidney.

Regulation of PTH secretion
Secretion of parathyroid hormone is controlled chiefly by serum [Ca2+] through negative feedback. is_associated_with::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 is_associated_with::brain, is_associated_with::heart, is_associated_with::skin, is_associated_with::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 is_associated_with::phospholipase C. This hydrolyzes is_associated_with::phosphatidylinositol 4,5-bisphosphate (PIP2) to liberate intracellular messengers IP3 and is_associated_with::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 is_associated_with::Hypomagnesemia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.

Stimulators

 * 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

 * Increased serum [Ca2+].
 * Severe decreases in serum [Mg2+], which also produces symptoms of is_associated_with::hypoparathyroidism (such as is_associated_with::hypocalcemia).
 * Calcitriol
 * Calcitriol

Clinical significance

 * is_associated_with::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 is_associated_with::hypoparathyroidism and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.


 * There are a number of rare but well-described genetic conditions affecting parathyroid hormone metabolism, including is_associated_with::pseudohypoparathyroidism, is_associated_with::familial hypocalciuric hypercalcaemia, and autosomal dominant hypercalciuric hypocalcaemia.


 * In osteoporotic women, administration of an exogenous parathyroid hormone analogue (is_associated_with::teriparatide, by daily injection) superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45 to 65%.

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 8–51 pg/ml.

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

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