Biochemical and Biophysical Research Communications
ReviewParathyroid hormone and parathyroid hormone-related peptide, and their receptors
Section snippets
Parathyroid hormone
PTH is a circulating hormone comprised of 84 amino acids. It is produced in the parathyroid glands and acts primarily on bone and kidney to maintain extracellular calcium levels within normal limits. Bovine PTH was initially purified and sequenced by two independent groups [1], [2], and the cDNA encoding bovine PTH was subsequently isolated by Kronenberg et al. [3] (Fig. 1). PTH is secreted from the chief cells of the parathyroid glands primarily in response to low extracellular calcium, but
Parathyroid hormone-related peptide
Early on it was noted that patients with various tumors had increased levels of serum calcium and elevated urinary cAMP excretion, despite low levels of PTH [7]. This condition, named the humoral hypercalcemia of malignancy syndrome, was subsequently determined to be the result of increased PTHrP secretion by the tumors [8], [9], [10], [11]. In humans, PTHrP is comprised of either 141 amino acids, or due to alternative mRNA splicing, 139 or 173 amino acids [12]. PTHrP shares significant
Receptors for PTH and PTHrP
PTH and PTHrP act through a common receptor, the PTH/PTHrP receptor [18], which is a class B G-protein-coupled receptor (Fig. 2). This family of receptors includes the receptors for secretin, vasoactive intestinal peptide, glucagon, glucagon-like peptide, corticotrophin-releasing factor, growth hormone-releasing hormone, pituitary adenylate cyclase-activating peptide, gastric inhibitory peptide, calcitonin, and a few other peptide hormones [19]. The N-terminal 34 amino acids of PTH and PTHrP
Structure of the ligands and the PTH/PTHrP receptor
PTH is synthesized as a pre-pro-hormone. The first 25 residues of the pre-sequence form a hydrophobic domain which is important for passage through the membrane of the endoplasmic reticulum [35]. The pro-sequence of six residues terminates in a dibasic cleavage site and is removed before the hormone is routed to secretory vesicles [36].
The secondary and tertiary structure of PTH(1–34) has been a matter of considerable debate. Functional studies based on the effects of single amino acid
Ligand–receptor interactions
Several lines of investigation have yielded information regarding possible modes of ligand–receptor interaction at the PTH/PTHrP receptor. As a result of these studies, PTH(1–34) (as well as PTHrP(1–36)) is thought to interact with the PTH/PTHrP receptor through distinct binding and activation domains (see Fig. 3A). Early evidence for this model came from studies with ligand and/or receptor chimeras, which indicated that the critically important N-terminal portion of the ligand interacts with
PTH and PTHrP in other species
Several teleost fish have been investigated for PTH ligands and receptors, and these studies have revealed at least two forms of PTH [83], [84], PTHrP [85], [87], and several PTH/PTHrP receptors [86], [87]. The reasons for this increased genetic complexity, and the biological roles for PTH and PTHrP in fish, have not yet been elucidated. Fish also have TIP39 [88] and the PTH2 receptor [87]; so far, only one gene has been identified for each of these proteins. Studies of PTH ligands and PTH
Receptor signaling
The activated PTH/PTHrP receptor initiates a cascade of intracellular processes primarily by signaling through the α-subunit of the stimulatory G-protein, Gsα [89], which in turn increases synthesis of cAMP and activates protein kinase A [90]. However, there are additional signaling pathways that the PTH/PTHrP receptor can utilize. For example, the receptor can signal through Gqα, and thus activate phospholipase C [91] and increase intracellular inositol trisphosphate and intracellular free
Diseases caused by mutations affecting PTH or the PTH/PTHrP receptor
The central roles of PTH, PTHrP, and the PTH/PTHrP receptor in calcium homeostasis and in the regulation of growth plate chondrocytes differentiation are illustrated by the various mutant mouse strains and clinical syndromes associated with mutations affecting these proteins and/or proteins involved in normal parathyroid gland development and PTH/PTHrP receptor signaling. For example, in mice ablation of the gene “glial cell missing 2” (Gcm-2), encoding a transcription factor, results in
PTH-based pharmaceutical agents
While sustained elevation of PTH levels leads to bone erosion, it has long been known that pulsatile administration of PTH results in increased bone formation [114]. This anabolic effect of PTH is now the basis for the clinical use of PTH(1–34) in the treatment of osteoporosis [115], [116]. Unfortunately, like most short bioactive peptides, PTH shows no efficacy after oral administration; its anabolic effect thus depends on administration of daily injections. The discovery of a minimal-length
Summary
PTH, PTHrP, and the PTH/PTHrP receptor have critical roles in many diverse biological systems, including calcium regulation, cell proliferation, and cell differentiation. Mutations in the genes encoding these proteins are responsible for several human diseases. PTH(1–34) is currently being used in the treatment of osteoporosis, and development of new PTH agonists or antagonist for human use may provide medical alternatives for treatment of osteoporosis, primary hyperparathyroidism, the humoral
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