Parathyroid hormone

The human PTH gene is located on chromosome 11 (11p15.3-p15.1). The human PTH and chicken pth genes comprise two introns that divide the gene into three exons, encoding the 50 -untranslated region (UTR), the signal peptide, the mature peptide, and the 30 -UTR. The pth gene structures of pufferfish are similar to those of tetrapods, which include three exons divided by two introns.

Extracellular calcium is the primary regulator of PTH secretion from the parathyroid gland. In mammals and birds, the circulating levels of PTH are greatly altered by minute changes in the blood calcium concentration. PTH secretion is modulated by the action of the calcium-sensing receptor (CaSR), which is located in the parathyroid gland. Under hypercalcemic conditions, Ca2+ binding to CaSR inhibits PTH secretion. Whereas, under hypocalcemic conditions, the receptor is not occupied by extracellular Ca2+, resulting in PTH secretion. In addition, 1,25(OH)2D3 acts directly on the parathyroid gland and suppresses the transcription rate of the PTH gene.

The organization of the PTH1 receptor (PTH1R) gene is highly homologous in three mammalian species, namely the rat, human, and mouse. This gene extends over 22 kb and contains at least 15 exons and 14 introns. The human gene was mapped to chromosome 3p21.1- p22. Both PTH and parathyroid hormone-related protein (PTHrP) bind to the PTH1R. As both peptides signal through the same receptor, it is also called the PTH/ PTHrP receptor. In contrast, the PTH receptor type 2 (PTH2R) is not activated by PTHrP but by PTH and a tuberoinfundibular peptide of 39 amino acids (TIP39). TIP39 is known as a ligand of PTH2R, although the similarity of sequence between TIP39 and PTH is low. In addition to PTH1R and PTH2R, zebrafish and other teleosts possess a third receptor, PTH3R, which may be derived by the duplication of PTH1R. PTHRs share the same basic structure (seven transmembrane domains) with that of the class B G-protein coupled receptor (GPCR) superfamily. A defining feature of the class B receptors is the relatively long extracellular N-terminal domain, which comprises approximately 150 amino acids and is important for ligand binding. The presence of six cysteine residues that are strictly conserved within the N-terminal domain of all class B GPCRs suggests that three disulfide linkages are present and are of critical importance. Kd in human kidney plasma membrane, canine kidney plasma membrane, and chick bone cell membrane is 1–5 nM.

The complete molecule is not essential to exert a biological effect. The N-terminal fragments of PTH and PTHrP, comprising amino acids 1–34, have biological activities similar to those of the complete molecules. PTH (1–14) and PTH (1–21) analogs show high-affinity binding and efficient activation of the PTH1R. [Leu11, D-Trp12] PTHrP (7–34) and [Ile5 , Trp23] PTHrP (5–36) bind with high affinity to PTH1R but are devoid of signaling activity. The PTH2R agonist, TIP39, binds efficiently to the PTH1R but does not activate it, and thus functions as a weak antagonist at this receptor.

First hormone isolated from the parathyroid gland to have hypercalcemic action. PTH is a drug target for hypoparathyroidism and osteoporosis. The presence of PTH in the parathyroid gland was reported in 1925. It was isolated in 1970 from bovine parathyroid glands. It was believed that PTH was absent in fish because the parathyroid gland is thought to appear when ancestral amphibians evolved. However, PTH was first identified from the fugu genome database in 2003, and thereafter the existence of PTH has been established in fish.

PTH is a single-chain polypeptide composed of 84 amino acid residues that is devoid of disulfide bonds and has a molecular weight of 9500. Biological activity of the human hormone resides primarily in the amino terminal end of the protein (i.e., amino acids 1–34).This portion of PTH has full biological activity both in vivo and in vitro. Synthetic fragments of the 1-34 portion of the PTH molecule have been synthesized. A paraneoplastic hormone, PTH related peptide (PTHrP) has been identified, isolated, and synthesized. PTHrP is structurally homologous to the amino terminal portion of PTH and interacts with the PTH receptor in bone and kidney. This hormone is responsible for hypercalcemia in certain forms of malignancy. It has been used as a therapeutic agent in osteoporosis in some clinical trials.

Mammalian PTHs: Mr. 9500. It is soluble in water and stable in a solution at pH 4.5. PTH in the collected blood is relatively unstable and hydrolyzes easily during storage. It is recommended that blood samples for PTH measurement should be taken using tubes containing EDTA and plasma should be separated within 24 h.

Treatment of osteoporosis, as an antiosteoporotic, in the treatment of bone and mineral disease and disorders, bone metabolism regulator, blood calcium regulator, and as a diagnostic aid (pseudohypoparathyroidism; hypocalcemia).

PTH is secreted from the parathyroid glands in response to a low plasma concentration of ionized (free) calcium. PTH immediately causes the transfer of labile calcium stores from bone into the bloodstream. PTH increases rates of dietary calcium absorption by the intestine indirectly via the vitamin D₃ system activation of enterocyte activity.Within the kidney, PTH directly stimulates calcium reabsorption and a phosphate diuresis.

Paroidin (Parke-Davis).

Plasma calcium concentration is the principal factor regulating PTH synthesis and release. The increase in PTH synthesis and secretion induced by hypocalcemia is believed to be mediated through activation of parathyroid gland adenylyl cyclase and a subsequent increase in intracellular cyclic adenosine monophosphate (cAMP).
Formation of PTH begins with the synthesis of several precursor molecules. PreproPTH is the initial peptide that is synthesized within the parathyroid gland, and it serves as a precursor to both proPTH and PTH. PreproPTH is formed within the rough endoplasmic reticulum, transported into the cisternal space, and then cleaved to form proPTH. The proPTH polypeptide is transported into the cisternal space, where another proteolytic cleavage occurs, forming PTH.

Parathyroid hormone (PTH) is biosynthesized as a 115-amino-acid preprohormone in the rough endoplasmic reticulum of the parathyroid gland and is cleaved to the prohormone (84 amino acids) in the cisternal space of the reticulum. The active hormone is finally produced (34 amino acids; molecular weight, 9,500 dalton) in the Golgi complex and is stored in secretory granules in the parathyroid gland. This gland is exquisitely sensitive to serum calcium concentrations and is able to monitor these levels via calcium-sensing receptors (CaSR). These cell surface receptors help cells to react to micromolar changes in the concentration of ionized calcium in the serum. Binding of calcium to these receptors facilitates activation of phospholipase C and, ultimately, inhibition of PTH secretion. The relatively short-acting PTH is secreted from the parathyroid gland chief cells in response to a hypocalcemic state and serves to oppose the hormonal effects of calcitonin.

PTH (parathyroid hormone), which are called calciotropic hormones. PTH controls the serum plasma level of Ca²⁺ by regulating the re-absorption ofCa²⁺ in the nephron, stimulating the uptake of Ca²⁺ from the gut and releasing Ca²⁺ from the bones which act as a reservoir.

Unlike calcitonin, the biological activity of PTH resides solely in residues 1 to 34 in the amino terminus. Parathyroid hormone decreases renal excretion of calcium, indirectly stimulates intestinal absorption of calcium, and in combination with active vitamin D, promotes bone resorption by a complex, unknown mechanism, thereby elevating serum calcium concentrations. In addition, the secretion of PTH stimulates the biosynthesis and release of the third hormone associated with calcium homeostasis, vitamin D. When serum calcium concentrations are high, the release of PTH is inhibited

Treatment of chronic hypoparathyroidism

diagnose a variety of calcium metabolic disorders, such as hyperparathyroidism, hypoparathyroidism, hypercalcaemia of malignancy, and chronic renal failure. The skeletal actions of PTH are dependent on the pattern of its administration.12 Intermittent exposure to PTH leads to a net increase in bone formation, whereas its continuous administration produces bone loss. Thus, the bone anabolic capability of PTH strictly depends upon its administration producing a transient peak level in plasma. PTH is used for osteoporosis therapy because of its ability to increase osteoblastogenesis and osteoblast survival. Furthermore, PTH is involved in the proliferation and differentiation of chondrocytes because mutations in the PTH1R have been identified in Jansen-type metaphyseal chondrodysplasia and Blomstrand-type lethal chondrodysplasia.

Potentially hazardous interactions with other drugs
Bisphosphonates: reduction of calcium-sparing effect with alendronate - avoid.

Parathyroid hormone is metabolised in the liver and to a lesser degree in the kidney. Parathyroid hormone is not excreted from the body in its intact form. Circulating carboxy-terminal fragments are filtered by the kidney, but are subsequently broken to even smaller fragments during tubular reuptake.
Parathyroid hormone is efficiently removed from the blood by a receptor-mediated process in the liver and is broken down into smaller peptide fragments. The fragments derived from the amino-terminus are further degraded within the
These carboxy-terminal fragments are thought to play a role in the regulation of parathyroid hormone activity

PTH is a single-chain nonglycosylated peptide. In humans, PTH is synthesized as a 115-aa precursor polypeptide. The signal peptide is cleaved, and the mature peptide is packed in secretory vesicles and then secreted as an 84-aa peptide . Chicken PTH consists of 88 aa with a striking similarity to the mammalian PTHs in the N-terminus. In the zebrafish and pufferfish, two PTH genes and one PTH-like protein gene have been discovered. In addition, the elephant shark has PTH1 and PTH2, although questions are left unanswered about the classification of these hormones in the PTH/PTHrP family. The mature PTH in mammals comprises an 84-aa peptide, the sequence of which varies in nonmammalian vertebrates. Among teleost fish, humans, and chickens, the amino acid identity of mature PTHs is around 20%–25% and the sequence similarity is close to 40%. However, high sequence conservation is observed among the first 34N-terminal amino acid residues of all PTHs.