Review
Parathyroid hormone and parathyroid hormone-related peptide, and their receptors

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Abstract

Parathyroid hormone (PTH) has a central role in the regulation of serum calcium and phosphate, while parathyroid hormone-related peptide (PTHrP) has important developmental roles. Both peptides signal through the same receptor, the PTH/PTHrP receptor (a class B G-protein-coupled receptor). The different biological effects of these ligands result from their modes of regulation and secretion, endocrine vs. paracrine/autocrine. The importance of PTH and PTHrP is evident by the variety of clinical syndromes caused by deficiency or excess production of either peptide, and the demonstration that intermittent injection of PTH increases bone mass, and thus provides a means to treat osteoporosis. This, in turn, has triggered increased interest in understanding the mechanisms of PTH/PTHrP receptor action and the search for smaller peptide or non-peptide agonists that have efficacy at this receptor when administered non-parenterally.

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

References (116)

  • A. Bazarsuren

    In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor

    Biophys. Chem.

    (2002)
  • C. Bergwitz

    Full activation of chimeric receptors by hybrids between parathyroid hormone and calcitonin

    J. Biol. Chem.

    (1996)
  • T.J. Gardella

    Converting parathyroid hormone-related peptide (PTHrP) into a potent PTH-2 receptor agonist

    J. Biol. Chem.

    (1996)
  • P.R. Turner

    Transmembrane residues together with the amino terminus limit the response of the parathyroid hormone (PTH) 2 receptor to PTH-related peptide

    J. Biol. Chem.

    (1998)
  • V. Behar

    Photoaffinity cross-linking identifies differences in the interactions of an agonist and an antagonist with the parathyroid hormone/parathyroid hormone-related protein receptor

    J. Biol. Chem.

    (2000)
  • A. Bisello

    Parathyroid hormone-receptor interactions identified directly by photocross-linking and molecular modeling studies

    J. Biol. Chem.

    (1998)
  • R.C. Gensure

    Identification of determinants of inverse agonism in a constitutively active parathyroid hormone/parathyroid hormone-related peptide receptor by photoaffinity cross-linking and mutational analysis

    J. Biol. Chem.

    (2001)
  • P.H. Carter

    The hydrophobic residues phenylalanine 184 and leucine 187 in the type-1 parathyroid hormone (PTH) receptor functionally interact with the amino-terminal portion of PTH-(1–34)

    J. Biol. Chem.

    (1999)
  • M. Mannstadt

    Evidence for a ligand interaction site at the amino-terminus of the parathyroid hormone (PTH)/PTH-related protein receptor from cross-linking and mutational studies

    J. Biol. Chem.

    (1998)
  • R.C. Gensure et al.

    Multiple sites of contact between the carboxyl-terminal binding domain of PTHrP-(1–36) analogs and the amino-terminal extracellular domain of the PTH/PTHrP receptor identified by photoaffinity cross-linking

    J. Biol. Chem.

    (2001)
  • M. Shimizu et al.

    Autoactivation of type-1 parathyroid hormone receptors containing a tethered ligand

    J. Biol. Chem.

    (2000)
  • M. Shimizu et al.

    Minimization of parathyroid hormone. Novel amino-terminal parathyroid hormone fragments with enhanced potency in activating the type-1 parathyroid hormone receptor

    J. Biol. Chem.

    (2000)
  • N. Shimizu et al.

    Parathyroid hormone (PTH)-(1–14) and -(1–11) analogs conformationally constrained by alpha-aminoisobutyric acid mediate full agonist responses via the juxtamembrane region of the PTH-1 receptor

    J. Biol. Chem.

    (2001)
  • T.J. Gardella

    Mutational analysis of the receptor-activating region of human parathyroid hormone

    J. Biol. Chem.

    (1991)
  • D.A. Rubin et al.

    Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide

    J. Biol. Chem.

    (1999)
  • D.A. Rubin

    A G protein-coupled receptor from zebrafish is activated by human parathyroid hormone and not by human or teleost parathyroid hormone-related peptide. Implications for the evolutionary conservation of calcium-regulating peptide hormones

    J. Biol. Chem.

    (1999)
  • D. Miao

    Parathyroid hormone-related peptide stimulates osteogenic cell proliferation through protein kinase C activation of the Ras/mitogen-activated protein kinase signaling pathway

    J. Biol. Chem.

    (2001)
  • A. Iida-Klein

    Mutations in the second cytoplasmic loop of the rat parathyroid hormone (PTH)/PTH-related protein receptor result in selective loss of PTH-stimulated phospholipase C activity

    J. Biol. Chem.

    (1997)
  • J. Guo

    The PTH/PTHrP receptor can delay chondrocyte hypertrophy in vivo without activating phospholipase C

    Dev. Cell

    (2002)
  • H.D. Niall

    The amino acid sequence of bovine parathyroid hormone I

    Hoppe Seylers Z. Physiol. Chem.

    (1970)
  • H.B. Brewer et al.

    Bovine parathyroid hormone: amino acid sequence

    Proc. Natl. Acad. Sci. USA

    (1970)
  • H.M. Kronenberg

    DNA complementary to parathyroid mRNA directs synthesis of pre-proparathyroid hormone in a linked transcription–translation system

    Nature

    (1977)
  • H. Murer et al.

    The sodium phosphate cotransporter family SLC34

    Pflugers Arch.

    (2004)
  • M.F. Pfister

    Parathyroid hormone leads to the lysosomal degradation of the renal type II Na/Pi cotransporter

    Proc. Natl. Acad. Sci. USA

    (1998)
  • A.F. Stewart

    Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups

    N. Engl. J. Med.

    (1980)
  • J.M. Moseley

    Parathyroid hormone-related protein purified from a human lung cancer cell line

    Proc. Natl. Acad. Sci. USA

    (1987)
  • G.J. Strewler

    Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone

    J. Clin. Invest.

    (1987)
  • L.J. Suva

    A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression

    Science

    (1987)
  • D.W. Brandt et al.

    Parathyroid hormone-like protein: alternative messenger RNA splicing pathways in human cancer cell lines

    Cancer Res.

    (1994)
  • H.M. Kronenberg

    Developmental regulation of the growth plate

    Nature

    (2003)
  • M.C. Neville et al.

    Hormonal regulation of mammary differentiation and milk secretion

    J. Mammary Gland Biol. Neoplasia

    (2002)
  • J. VanHouten

    The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport

    J. Clin. Invest.

    (2004)
  • C.P. Rodda

    Evidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy

    J. Endocrinol.

    (1988)
  • C.S. Kovacs

    Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor

    Proc. Natl. Acad. Sci. USA

    (1996)
  • H. Jüppner

    A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide

    Science

    (1991)
  • L.F. Kolakowski Jr., GCRDb: a G-protein-coupled receptor database. Receptor Channels 2(1)...
  • T.B. Usdin

    TIP39: a new neuropeptide and PTH2-receptor agonist from hypothalamus

    Nat. Neurosci.

    (1999)
  • C.J. LaBuda et al.

    Tuberoinfundibular peptide of 39 residues decreases pain-related affective behavior

    Neuroreport

    (2004)
  • Y. Sugimura

    Centrally administered tuberoinfundibular peptide of 39 residues inhibits arginine vasopressin release in conscious rats

    Endocrinology

    (2003)
  • T.B. Usdin et al.

    The parathyroid hormone 2 (PTH2) receptor

    Receptors Channels

    (2002)
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