The existence of PTHrP was first encountered as a consequence of the disease of humoral hypercalcemia of malignancy (HHM). In HHM, patients have significantly elevated serum Ca2+ levels and a tumor that secretes PTHrP. Surprisingly, the same gene and receptor protein services both PTH and PTHrP. Thus, as emphasized in Figure 1, PTHrP actually has a wider sphere of actions than does PTH. Although PTH and PTHrP are quite different proteins (see Figure 2), because of their high structural homology over the first 13 amino acids, both hormones, utilizing the second messenger, cAMP, can generate PTH-like biological responses in bone and kidney.

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.

Fig2. Comparison of the gene intron/exon organization and the protein size and amino acid length of Pre-Pro-, Pro- for the secreted parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). The gene for PTH and PTHrP are respectively found on chromosome 11p and 12p. In comparison to the gene for PTHrP which has 9 exons, the PTH gene has only 3 exons. The secreted and mature forms of PTH and PTHrP each have their own color. The secreted PTH has 84 amino acids, but, as indicated by cross-hatching, all the biological activity resides in the first 34 amino acids. Both the PTH and PTHrP bind to the same G-protein coupled receptor (see Figure 1) to generate their diverse biological responses. The secreted PTHrP has 141 amino acids; after residue 13 there is no sequence homology with PTH. However, the first 13 amino acids of PTH and PTHrP are virtually identical (see bottom of figure).

PTHrP is known to be synthesized in several tis sues (growth plate of bone, placenta, breast, skin, hair, teeth) with most of its actions and biological responses being of a paracrine nature. PTHrP is involved with Ca2+ transport associated with pregnancy and lactation. Peptide fragments of PTHrP are able to stimulate Ca2+ transfer across the placenta to the fetus. In lactating mice, the secretion of PTHrP from the breast results in an increase of bone resorption which increases the serum Ca2+ concentration. This Ca2+ increase signals to the breast’s calcium receptor (CaR) which then sends a second messenger to breast cells that results in an increase in the movement of Ca2+ into milk and at the same time a downregulation of PTHrP secretion.

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مواضيع ذات صلة

Calcitonin Receptor and Biological Actions

Parathyroid Hormone 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