The major target organs for PTH actions are kidney and bone. PTH may also act upon the intestine, but its effects here are indirect and are achieved by virtue of the tropic actions of PTH in stimulating the renal bio synthesis of 1α,25(OH)2D3.

The secretion of PTH is stimulated in response to a lowered blood concentration of calcium (see Figure 1). In terms of the several forms of blood calcium summarized in Table 1, it is known that the biosynthesis and secretion of PTH are only responsive to the ionic and not to the protein-bound forms of calcium. The secretion of PTH can be stimulated when hypocalcemia is induced by the infusion of calcitonin or the divalent metal-chelating agent, EDTA (ethylene-damine-tetraacetic acid), or decreased when hypercalcemia is induced by the infusion of calcium. Thus, there is an inverse correlation between serum calcium concentration and PTH con centration in the range of 4–10 mg of calcium/100 mL (Figure 1). The most stringent control of serum calcium concentration is achieved in the range of 9–10.5 mg of Ca2+/100 mL of serum, which is considered to be the normal physiological range of this divalent cation. Serum concentrations of calcium that fall above or below this range are likely to be due to the presence of disease states that perturb the integrated calcium–phosphorus homeostatic mechanisms.

Fig1. Changes in plasma levels of immunoreactive parathyroid hormone (iPTH) and calcitonin (iCT) as a function of plasma total calcium. The data were obtained in pigs given EDTA to decrease plasma calcium or given calcium infusions to increase plasma calcium. Note that, as serum calcium increases, iPTH falls and serum iCT increases; as serum calcium decreases the reverse occurs. Reproduced with permission of Arnaud, C. D. et al. (1970). In Calcitonin: Proceedings of the Second International Symposium (S. Taylor, ed.). Heinemann, London, p. 236.

Table1. Distribution of Calcium and Phosphate in Normal Human Plasma ^a

A key signal transduction question is related to the identification of the mechanism(s) by which the plasma membrane of a parathyroid cell can sense a fall or rise in the ambient extracellular ionized calcium concentrations and signal either the secretion of PTH or inhibition of PTH secretion. A G-protein coupled Ca2+ sensing receptor (CaR) from bovine parathyroid tissue and then a human adenoma were cloned and sequenced in 1993 and 1995, respectively. The human CaR is a 120-kDa protein (1078 amino acids) and features a large extracellular domain (612 amino acids) with clusters of acidic amino acid residues likely involved in Ca2+ binding. The seven-membrane-spanning domain encompasses 249 amino acids followed by the 216 intracellular amino acid sequence that translates the activation of the signal transduction response into release of a second messenger. The CaR is present as a homo dimer. The CaR senses the ionized extracellular Ca2+ concentration and generates an intracellular signal transduction activation inside the cell of several phospholipases (C, A2 and D), or mitogen activated protein kinase (MAP kinase) or inhibition of adenylate kinase; despite major efforts, the details of the second messenger generation remain elusive.

The secretion of PTH by the parathyroid gland cells is regulated by changes in the stability of the PTH mRNA. The CaR present in the plasma membrane of a PTH secretory cell can differentiate between hypocalcemia and hypercalcemia and send an appropriate second messenger to increase the stability of the PTH mRNA (hypocalcemia) or decrease the stability of the PTH mRNA (hypercalcemia); see Figure 2. The mediator of changes in the stability of the PTH mRNA is Pin1, a peptidyl- cis-trans isomerase. Pin1 responds to the incoming second messenger from the CaR and generates one of two possible changes in the properties of the regulatory KSRP protein, which is a PTH mRNA binding protein: (a) In the instance of elevated serum Ca2+, KSRP becomes dephosphorylated which enables the Pin1 isomerase to mediate a conformational change in the KSRP protein, allowing it to bind to the PTH mRNA nucleotide ARE motif and thereby reducing the stability of the PTH mRNA; this lowers the concentration of PTH mRNA and therefore reduces the secretion of PTH; (b) In the instance that KRSP becomes phosphorylated, which blocks its ability to bind to the PTH mRNA thereby increasing the stability of the PTH mRNA, an increase in the concentration of PTH mRNA is caused which increases the secretion of PTH. Further details are provided in the legend to Figure 2.

Fig2. Regulation of PTH secretion via changes in stability of the PTH messenger RNA. The plasma membrane Ca2+ receptor of the PTH secreting cell senses changes in the serum Ca2+ level through a seven-transmembrane G protein linked to phospholipases that sends a second messenger to the cellular site of the regulation of the PTH mRNA concentration (see the two gold stars). Changes in the rate of secretion of PTH PTh secreting cells are mediated by changing the stability of the PTH mRNA. In the inset below the cell, there are two schematic diagrams of the PTH mRNA from 5′-UTR to 3′-UTR. The More stable mRNA schematic illustrates the circumstance of hypocalcemia, resulting in an increase in the stability of PTH mRNA and ultimately greater PTH secretion. The Less stable mRNA schematic illustrates the circumstance of hypercalcemia (with associated low serum phosphate) resulting in reduction of PTH mRNA stability and ultimately lower PTH secretion. Two key regulatory proteins (UNR and AUF1) bind to the 3′ untranslated region (3′UTR) of the PTH mRNA stabilizing PTH mRNA levels necessary to increase PTH secretion. In contrast, the K homology-type Splicing Regulatory Protein (KSRP) also binds to the PTH mRNA 3′-UTR, specifically to the ARE (Adenine- and uridine-Rich Elements) which is a conserved 26 nucleotide sequence that decreases PTH mRNA stability and as a consequence reduces PTH secretion. When KSRP is phosphorylated on serine-181 it cannot bind to the 3′-UTR ARE region (More stable mRNA) and there is no reduction of PTH mRNA stability and accordingly PTH secretion is increased. But when KSRP is not phosphorylated, it can bind (Less stable mRNA) to the PTH mRNA 3′-UTR ARE region, thus decreasing PTH mRNA stability and thereby reducing the secretion of PTH. Pin1 is a peptidyl- cis-trans isomerase that specifically binds to the unphosphorylated Ser/Thr-Pro protein motif of KSRP. This catalyzes the cis/trans isomerization of the KSRP proline peptide bonds, thus causing a conformational change in KSRP and increasing the biological activity of KSRP so that it can bind to the ARE nucleotide sequence of the PTH mRNA, which then results in a decrease in both the stability of the PTH mRNA and the secretion of PTH. The PTH secreting cell also has receptors for both 1α,25(OH)2D3 (produced by the kidney) and FGF-23 (produced by bone). Both hormones downregulate PTH gene transcription, thus lowering PTH production and secretion.

All of the main biological actions of PTH are mediated by its interaction with the PTH receptor (see Figure 3) which collectively increases the Ca2+ concentration of the blood compartment. The most important bio logical actions of PTH are the following: (a) to increase the rate of conversion of 25(OH)D3 to 1α,25(OH)2D3 in kidney tissue and, thus, increase the serum concentration of 1α,25(OH)2D3 which will increase intestinal Ca2+ absorption; (b) to increase the plasma Ca2+ concentration by the action of the proximal convoluted tubule via stimulating reabsorption of Ca2+ from the kidney glomerular filtrate; (c) to increase the number of osteoclasts and thus the extent of osteoclastic and osteocytic osteolysis in bone (bone resorption and remodeling); and (d) to increase the urinary excretion of phosphate by inhibiting the renal tubular reabsorption of phosphate. Further details are provided in the legend to Figure 2.

Fig3. Both the parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are ligands for the same receptor yet produce diverse biological responses. PTH (but not PTHrP) acts as a classic hormone and binds to its receptor (lavender boxes), in bone osteoblasts and kidney cells, while PTHrP (but not PTH) acting as an autocrine/paracrine messenger binds to its receptor (blue box) in cartilage, teeth, breast, skin, pancreas cells. The PTH/PTHrP receptor is a G-protein coupled receptor. When either PTH or PTHrP are bound to their receptor (shown in magenta as a 7-membrane receptor), there are two main pathways of response: (a) activation of adenyl cyclase via Gsα leading to cAMP and activation of protein kinase A (PKA); or (b) activation of phospholipase C (PLC) to produce IP3+diacylglycerol (DAG) that lead to an increase in intracellular Ca2+ concentrations and activation of protein kinase C (PKC), respectively.

The opossum kidney cell PTH receptor has been cloned, sequenced, and found to be a member of a distinct family of G-protein-coupled receptors with seven-transmembrane-spanning domains. The mature receptor protein contains 585 amino acids. The PTH receptor (PTH) and the PTH-related receptor (PTHrP) have been found to be the same protein (Figure 3). The amino acid sequence of PTH and PTHrP are identical over the first 13 residues which is expressed in both kidney and osteoblast cells, which are prime targets for PTH action, and also in aorta, brain, heart, ileum, liver, placenta, skin, uterus, and testes.

Both PTH and PTHrP bind with equal affinity to the cloned and expressed receptor, and both ligands equivalently stimulate adenyl cyclase (see Figure 3). Intriguingly, there is close structural homology between the PTH receptor, the PTHrP receptor, the calcitonin receptor, and the “secretin” subfamily of closely related receptors. Other family members include secretin, vasoactive intestinal polypeptide (VIP), and glucagon receptors. For all of these proteins, receptor occupancy by its cognate ligand results in activation of adenyl cyclase and, in some instances, increases in the concentration of intracellular Ca2+.

The actions of PTH on bone are complex and continue to be an area of intense investigation. The response of bone to PTH is biphasic; the immediate action is largely that of bone mineral mobilization (i.e., an elevation of the blood levels of both calcium and phosphate). These effects may be detected within minutes following hormone administration. A second and slower action of PTH is its effect upon bone cell activity. PTH has been shown to increase the number and size of the bone-resorbing osteoclasts. Although PTH is a potent bone-resorbing agent, receptors for PTH are not found on osteoclasts and are only present on osteoblasts. Also associated with prolonged bone resorption is an increased release of lysosomal enzymes by the osteoclasts, so that there is a breakdown and solubilization of the bone matrix. This generates two consequences: (a) removal of the proteolyzed bone matrix prepares the bone pit/cavity for replacement with both new bone matrix and calcium hydroxyapatite; and (b) the proteolyzed matrix is further broken down to small peptides that eventually increase the blood concentration of hydroxypro line. Elevated levels of blood and urine hydroxyproline concentrations are used as a marker for excessive bone resorption.

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مواضيع ذات صلة

Calcitonin Receptor and Biological Actions

Parathyroid Hormone-Related Protein Receptor and Biological Actions

T3 Inhibition of TSH and TRH Gene Expression

Mechanism of T3 Action

Role of Thyroid Hormone in Thermogenesis

Metabolism of Thyroid Hormone :Deiodination

Thyroid Hormone Transporters

Ghrelin, Leptin, and Energy Use

Coordination of Gastroenteropancreatic Hormone Release

Pancreatic, Biliary, and Intestinal Secretions

Hormone-Secreting Cells: Their Distribution in the Gastroenteropancreatic Complex

Leptin Functions as a Satiety Factor