Parathyroid hormone
Encyclopedia
Parathyroid hormone parathormone or parathyrin, is secreted by the chief cells
of the parathyroid gland
s 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). PTH half-life is approximately 4 minutes. It has a molecular mass of 9.4 kDa.
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.
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).
from the proximal tubule
of the 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.
[Ca2+] through negative feedback. Calcium-sensing receptor
s located on parathyroid cells are activated when [Ca2+] is low. 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 which 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.
The average PTH level is 10-60 pg/ml.
Parathyroid chief cell
Parathyroid chief cells are cells in the parathyroid glands which produce parathyroid hormone....
of the parathyroid gland
Parathyroid gland
The parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans usually have four parathyroid glands, which are usually located on the rear surface of the thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest...
s as a polypeptide containing 84 amino acids. It acts to increase the concentration of calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
(Ca2+) in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, whereas calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
(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). PTH half-life is approximately 4 minutes. It has a molecular mass of 9.4 kDa.
Structure
hPTH-(1-34) crystallizes as a slightly bent, long helical dimer. Analysis reveals that the extended helicalAlpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
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 serum calcium through its effects on the following tissues:| Region | Effect >- | bone Bone Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue... |
Bone resorption Bone resorption Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood.... is the normal destruction of bone by osteoclast Osteoclast An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873... s, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblast Osteoblast Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen... s, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their expression of Osteoprotegerin Osteoprotegerin Osteoprotegerin , also known as osteoclastogenesis inhibitory factor , or tumor necrosis factor receptor superfamily member 11B , is a protein that in humans is encoded by the TNFRSF11B gene... (OPG). OPG binds to RANKL RANKL Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is... 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 Bone resorption Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood.... . >- | kidney Kidney The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and... |
>- | It enhances the absorption of calcium in the intestine Intestine In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine... by increasing the production of activated vitamin D Vitamin D Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate .... . Vitamin D activation occurs in the kidney. PTH up-regulates 25-hydroxyvitamin D3 1-alpha-hydroxylase 25-Hydroxyvitamin D3 1-alpha-hydroxylase 25-Hydroxyvitamin D3 1-alpha-hydroxylase also known as cytochrome p450 27B1 is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene.... , the enzyme responsible for 1-alpha hydroxylation Hydroxylation Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air... 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 Calbindin Calbindin refers to several calcium-binding proteins. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals... . |
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).
Regulation of serum phosphate
PTH reduces the reabsorption of phosphatePhosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
from the proximal tubule
Proximal tubule
The proximal tubule is the portion of the duct system of the nephron of the kidney which leads from Bowman's capsule to the loop of Henle.-Structure and appearance:...
of the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
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 serumBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
[Ca2+] through negative feedback. Calcium-sensing receptor
Calcium-sensing receptor
The calcium-sensing receptor is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. In the parathyroid gland, the calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone .-Signal transduction:The release of PTH is...
s located on parathyroid cells are activated when [Ca2+] is low. 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 which 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
- 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 hypoparathyroidismHypoparathyroidismHypoparathyroidism is decreased function of the parathyroid glands with under production of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany , and several other symptoms...
(such as hypocalcemia).
Clinical significance
- A high level of PTH in the blood is known as hyperparathyroidismHyperparathyroidismHyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone . The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels...
.- If the cause is in the parathyroid gland it is called primary hyperparathyroidism. The causes are parathyroid adenomaAdenomaAn adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
, parathyroid hyperplasiaHyperplasiaHyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
and parathyroid cancer. - If the cause is outside the gland, it is known as secondary hyperparathyroidism. This can occur in chronic renal failureChronic renal failureChronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
. In secondary hyperparathyroidism, serum calcium levels are decreased, which causes the hypersecretion of PTH from the parathyroid glands. PTH acts on the proximal tubules in the kidney to decrease reabsorption of phosphate (increasing its excretion in urine, decreasing its serum concentration), but enhances active reabsorption of calcium and magnesium from distal tubules and the thick ascending limb. NOTE: in chronic renal failure, the failing kidneys are unable to excrete phosphate in the urine. In this case of secondary hyperparathyroidism, serum calcium will be decreased, but serum phosphate will be increased.
- If the cause is in the parathyroid gland it is called primary hyperparathyroidism. The causes are parathyroid adenoma
- A low level of PTH in the blood is known as hypoparathyroidismHypoparathyroidismHypoparathyroidism is decreased function of the parathyroid glands with under production of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany , and several other symptoms...
. Causes include surgical misadventureMisadventureMisadventure can refer to:* Ed, Edd n Eddy: The Mis-Edventures, a 2005 video game* The Misadventures of Merlin Jones, a 1964 Walt Disney film* The Misadventures of P.B...
(eg inadvertent removal during routine thyroid surgery), autoimmune disorder, and inborn errors of metabolism.
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
- Parathyroid hormone familyParathyroid hormone familyParathyroid hormone is a polypeptidic hormone that elevates calcium level by dissolving the salts in bone and preventing their renal excretion. The 'parathyroid hormone-related protein' is structurally related to PTH and seems to play a physiological role in lactation, possibly as a hormone for...
- Calcium metabolismCalcium metabolismCalcium metabolism or calcium homeostasis is the mechanism by which the body maintains adequate calcium levels. Derangements of this mechanism lead to hypercalcemia or hypocalcemia, both of which can have important consequences for health....
- Disorders of calcium metabolismDisorders of calcium metabolismDisorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body....
- Parathyroid hormone-related proteinParathyroid hormone-related proteinParathyroid hormone-related protein is a protein member of the parathyroid hormone family. It is occasionally secreted by cancer cells . However, it also has normal functions.- Function :PTHrP acts as an endocrine, autocrine, paracrine, and intracrine hormone...