1 Endocrine Unit, The type 1 receptor (PTH1R) for parathyroid hormone (PTH) and parathyroid
hormone-related peptide (PTHrP) is a G protein-coupled receptor that is highly expressed in bone and kidney and mediates in
these tissues the PTH-dependent regulation of mineral ion homeostasis. The PTH1R also mediates the paracrine actions of PTHrP,
which play a particularly vital role in the process of endochondral bone formation. These important functions, the likely involvement of
the PTH1R in certain genetic diseases affecting skeletal
development and calcium homeostasis, and the potential utility of PTH
in treating osteoporosis have been the driving force behind intense
investigations of both the receptor and its peptide ligands. Recent
lines of work have led to the identification of constitutively active
PTH1Rs in patients with Jansen's metaphyseal
chondrodysplasia, the demonstration of inverse agonism by certain
ligand analogs, and the discovery of the PTH-2 receptor subtype that
responds to PTH but not PTHrP. As reviewed herein, a detailed
exploration of the receptor-ligand interaction process is currently
being pursued through the use of site-directed mutagenesis and
photoaffinity cross-linking methods; ultimately, such work could enable
the development of novel PTH receptor ligands that have
therapeutic value in treating diseases such as osteoporosis and certain
forms of hypercalcemia.
parathyroid hormone; peptide hormone family; class II G
protein-coupled receptor; receptor binding; signal transduction; structure-activity relationship; receptor mutagenesis; photochemical
cross-linking; constitutively active receptor; receptor mutations in
human disease; parathyroid hormone-related peptide
IN MAMMALS, parathyroid hormone (PTH) is the most
important regulator of calcium ion homeostasis (62, 84). The peptide hormone is synthesized as a precursor protein containing a presequence of 25 amino acids and a prosequence of 6 amino acids, which are both
cleaved during the synthesis and secretion process to yield the mature
form of 84 amino acids. PTH is almost exclusively produced by the
parathyroid glands (small amounts of its mRNA have been detected in the
rat hypothalamus, Ref. 79), and its synthesis and
secretion is largely regulated by the extracellular concentration of
calcium, which is monitored by the calcium-sensing receptor of the
parathyroid glands (16). In response to low blood calcium levels, PTH
is secreted into the circulation and then acts primarily on kidney and
bone, where it binds to cells expressing the type 1 PTH/PTHrP receptor
(PTH1R). The ensuing direct and indirect responses of these target
cells help to maintain blood calcium concentrations to within narrow limits.
In kidney, PTH directly stimulates the tubular reabsorption of calcium,
and it stimulates the activity of 1 In addition to these regulatory actions on calcium homeostasis, PTH
helps to maintain blood phosphate concentration within normal limits by
inhibiting its reabsorption in proximal and distal tubules of the
kidney (15, 18). This is achieved by reducing, through several
different mechanisms, the expression levels of the sodium-dependent
cotransporter Npt2 (previously termed NaPi2) in the brush-border
membrane of the proximal tubules. This reduction in Npt2 results in
increased urinary losses of phosphate (70, 81). Although PTH exerts
important effects on renal phosphate handling, it is likely that other
factors, particularly dietary phosphate and a poorly characterized
humoral factor provisionally termed "phosphatonin," are more
important regulators of phosphate homeostasis (23).
PTH-related peptide (PTHrP) was first discovered as the most frequent
cause of the syndrome of humoral hypercalcemia of malignancy (71, 77,
97, 98, 101). However, PTHrP mRNA is widely expressed under normal
conditions, and gene ablation experiments have established that this
peptide plays an essential role in normal skeletal development (57).
Human PTHrP can be produced as a 141-amino acid peptide or, through
alternative mRNA splicing, as a protein comprising either 139 or 173 amino acids. PTHrP binds to the same receptor as PTH, and the
biological responses elicited by either ligand through this common
PTH1R are largely indistinguishable, at least with regard to mineral
ion homeostasis (24, 26, 43, 59). For these actions of PTH and PTHrP,
the amino-terminal (1-34) peptide fragments are sufficient, as
PTH-(1-34) and PTHrP-(1-34) display high-affinity receptor
binding and efficient receptor activation. There is a growing body of
evidence, however, suggesting that midregional and/or carboxy-terminal
fragments of either peptide, derived through posttranslational
processing mechanisms, also have biological activity (61, 84, 119).
However, the observed activities of midregional and
COOH-terminal fragments of PTH and PTHrP are unlikely to be related to
adult mineral ion homeostasis and are probably mediated through
receptors that are distinct from the PTH1R, although these receptors
have not yet been identified.
PTH and PTHrP show significant sequence homology within the first 13 amino acid residues (Fig. 1), and this
sequence conservation reflects the functional importance of the
amino-terminal residues in receptor signaling (38, 43, 44, 59, 107).
Between PTH and PTHrP, sequence homology decreases markedly in the
14-34 region, where only three amino acids are identical, and
beyond residue 34 there is no recognizable similarity. For both PTH and PTHrP, the 15-34 region functions as the principal PTH1R binding domain, and these portions of the two peptides probably interact with
overlapping regions of the receptor, as the two fragments compete
equally for binding with radiolabeled PTH-(1-34) or
PTHrP-(1-36) to the PTH1R (1, 17). These data also suggest that
the two divergent receptor-binding domains of PTH and PTHrP adopt
similar conformations.
ABSTRACT
INTRODUCTION
-hydroxylase and thereby
increases the 1,25-dihydroxyvitamim
D3
[1,25(OH)2D3]-dependent absorption of calcium from the intestine. In bone, PTH can induce a
rapid release of calcium from the matrix, but it also mediates longer-term changes in calcium metabolism by acting directly on osteoblasts and indirectly on osteoclasts, the bone-resorbing cells.
PTH action on osteoblasts leads to changes in the synthesis and/or
activity of several proteins, including osteoclast-differentiating factor, also known as TRANCE, RANKL, or osteoprotegerin ligand (86,
122).
PARATHYROID HORMONE-RELATED PEPTIDE
STRUCTURE-ACTIVITY RELATIONS IN PTH AND PTHRP
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Fig. 1.
Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) and analogs:
functional domains and receptor selectivity determinants.
A: amino acid sequences of the
bioactive (1-34) regions of native human PTH and human PTHrP. In
the schematic of human PTHrP, only residues that differ from human PTH
are provided, and amino acids that are identical to the corresponding
residues of PTH are represented by open circles. Bars represent peptide
fragments that exhibit weak receptor binding (15-34) or antagonist
and inverse agonist properties (7-34), as described in the text.
B: changing residues 5 and 23 in PTHrP
to the corresponding residue of PTH rescues the inability of native
PTHrP to bind to and stimulate cAMP formation in cells expressing the
PTH-2 receptor. Note that the PTH-1 receptor does not discriminate
between these analogs.
The three-dimensional crystal structures of PTH or PTHrP are not known,
but the peptides have been analyzed extensively by nuclear magnetic
resonance (NMR) spectroscopic methods. In general, these
studies indicate that, under certain solvent conditions, PTH-(1-34) and PTHrP-(1-36) analogs contain defined segments
of secondary structure, including a relatively stable -helix in the
carboxy-terminal receptor-binding domain, a shorter less stable helix
near the amino-terminal activation domain, and a flexible hinge or bend
region connecting the two domains (4, 73, 80). Although most NMR
solution studies find evidence for peptide flexibility, the question of
whether the conformations of PTH and PTHrP recognized by the receptor
are folded with tertiary interactions, as suggested by some studies (5,
20, 37), or extended, as suggested by other analyses (80), remains unanswered.
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RECEPTORS FOR PTH AND PTHRP |
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As indicated above, PTH and PTHrP mediate their actions primarily through the PTH1R PTH/PTHrP receptor, a G protein-coupled receptor (GPCR) with seven membrane-spanning helixes. The PTH1R forms, along with the receptors for secretin, calcitonin, glucagon, and several other peptide hormones, a distinct family of GPCRs that exhibit none of the amino acid sequence motifs found in the other subgroups of the superfamily of heptahelical receptors (49, 60, 93). These peptide hormone receptors, called class II or family B receptors (60), can be distinguished from other GPCRs by their large (~150 amino acid) amino-terminal extracellular domain containing six conserved cysteine residues, as well as by several other conserved amino acids that are dispersed throughout the NH2-terminal domain, the membrane-embedded helixes, and the connecting loops.
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PTH1R SIGNALING AND LIGAND INTERACTIONS |
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The PTH1R is considered to be a potentially important target for pharmacological interventions aimed at treating disorders of mineral ion homeostasis and the skeleton, such as hyperparathyroidism, humoral hypercalcemia of malignancy, and osteoporosis. Studies on ligand interactions with the PTH1R have largely focused on amino-terminal peptide hormone analogs, such as PTH-(1-34) and PTHrP-(1-34), as there is no evidence to suggest that midregional or carboxy-terminal portions of the intact ligands interact with this receptor (48, 83, 102). Stimulation of cells expressing the PTH1R by PTH-(1-34) or PTHrP-(1-34) agonist ligands can activate at least two second messenger signaling systems: the adenylyl cyclase/protein kinase A (AC/PKA) pathway and the phospholipase C/protein kinase C (PLC/PKC) pathway (84, 92). The classic PTH1R-mediated cAMP/PKA pathway has been widely studied in a variety of cellular settings and typically elicits a robust and sensitive response to agonist ligands. In comparison, agonist efficacy and potency profiles observed in assays of the PLC/PKC pathway are generally lower than those of the AC/PKA pathway (39, 47).
The roles of these two signaling pathways in mediating the downstream physiological effects of PTH and PTHrP are still poorly understood, but some progress has been made at deciphering the mechanisms by which the two signals are transduced at the membrane level. It has been well established that the determinants of cAMP/PKA signaling in the ligands PTH and PTHrP reside within the amino-terminal residues (38, 43, 59, 107); however, the ligand determinants of PLC/PKC activation have been more difficult to define. In some recent studies, a PTH-based tetrapeptide containing only residues 28-32 activated PKC activity in a rat osteosarcoma cell line (31, 51, 52); yet PTH analogs as short as 1-30 activated PLC in cells transfected with the recombinant rat or human PTH1R (103). Moreover, PTH-(3-34) was devoid of PLC-stimulating activity in similarly transfected cells (104). At present, the non-adenylyl-cyclase-mediated pathways appear more complex than the AC/PKA pathway and may involve multiple phospholipase isoforms (e.g., PLD and PLC), and be sensitive to variations in cell type, receptor density, and receptor species derivation (28, 103, 104).
The receptor sites involved in coupling to G proteins are currently being investigated by mutagenesis methods. For example, mutations in the second intracellular loop of the rat PTH1R selectively uncouple the Gq-linked pathway (e.g., PLC-signaling is impaired) without disrupting the Gs-linked activation of AC (46), and mutations in the third cytoplasmic loop uncouple both the Gs- and the Gq-linked pathway (45). Subsequent to G protein activation, the PTH1R becomes phosphorylated and desensitizes (12, 13, 69, 85), and an area of current investigation involves the use of novel receptor mutants and fluorescent microscopy techniques to define the biochemical linkages between these processes (105).
The mechanisms by which PTH and PTHrP bind to the PTH1R and then induce
the presumed conformational changes that lead to G protein coupling
have been explored through the use of receptor mutants and receptor
chimeras. Structurally altered PTH or PTHrP analogs have proven to be
of value in these studies by serving as functional probes of ligand
interaction sites in the receptor. For example, the antagonist
PTH-(7-34) bound to the human PTH1R with ~30-fold higher
affinity than it did to the rat PTH1R. Reciprocal pairs of rat/human
and human/rat receptor chimeras were used to identify receptor regions
involved in this binding selectivity, and the results identified the
amino-terminal extracellular domain as the major determinant (55).
Similarly, studies on the analog [Arg2]PTH-(1-34),
which is an agonist with the opossum PTH1R and an antagonist with the
rat PTH1R, revealed clues as to receptor residues involved in
recognizing the side chain of position 2 in the ligand. Thus
rat/opossum PTH1R chimeras and subsequent point
mutational analysis identified three divergent residues
near the extracellular ends of transmembrane helix 5 (TM5;
Ser370 and
Val371, rat PTH1R) and TM6
(Leu427, rat PTH1R) that determine
[Arg2]PTH-(1-34)
signaling specificity (Fig. 2) (33).
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The above functional studies on PTH1R mutants suggested a simple scheme
for the ligand-receptor interaction in which the carboxy-terminal region of PTH-(134) interacts with the amino-terminal extracellular domain of the receptor and that the amino-terminal portion of the
ligand interacts with the receptor region comprising the
membrane-spanning helixes and extracellular loops. As summarized below,
subsequent functional studies with other receptor variants that have
been evaluated with different PTH or PTHrP analogs, as well as recent photoaffinity cross-linking studies, have supported this scheme.
The type 2 PTH receptor (PTH2R) is 51% identical to the type 1 receptor and responds fully to PTH, but not at all, or very poorly, to PTHrP (113). The biological importance of the PTH2R, which is expressed in only a few tissues (112, 113), is currently unknown, but its unique ligand specificity has provided additional clues regarding ligand-receptor interaction sites. The analysis of PTH/PTHrP hybrid ligands revealed that Phe23 in PTHrP (Trp in PTH) prevents high-affinity binding to the PTH2R (36) and that the presence of His5 in PTHrP (Ile in PTH) blocked cAMP signaling (Fig. 1A) (6, 36). Subsequent studies in which single amino acids of the PTH2R were replaced with the corresponding residues of the PTH1R led to the identification of several new determinants of ligand specificity. In particular, Ile244, Tyr318, and Cys397, which are located in the PTH2R at the extracellular ends of TM3, TM5, or TM7, respectively (replaced by Leu289, Ile363, and Tyr443 in the human PTH1R, respectively), determined the receptor's ability to increase cAMP accumulation in response to PTHrP (Fig. 2) (8, 110). Furthermore, the data on Ile244 and Tyr318 suggested that these residues functionally interact with residue 5 of the ligand (8). In addition to these sites, it is likely that other receptor domains, including the amino-terminal extracellular region, play a role in conferring complete ligand selectivity to the PTH2R (8, 19, 110).
The general mode of ligand-receptor interaction suggested from the above studies on PTH receptors may well be used by the other class II peptide hormone receptors. In support of this notion, chimeras formed between the PTH1R and the calcitonin receptor selectively responded to PTH/calcitonin hybrid ligands, such that the COOH-terminal portion of the hybrid ligand corresponded to the NH2-terminal domain of the receptor, and the NH2-terminal portion of the ligand corresponded to the body of the receptor (7). Additional studies on chimeras formed between the receptors for glucagon, secretin, and vasoactive intestinal peptide are also consistent with this hypothesis (8, 19, 41, 42, 99, 109).
The use of photoreactive PTH and PTHrP analogs as chemical
cross-linking probes is providing a complementary approach to the mapping of ligand-receptor interactions by mutational methods. The
peptide analogs that have been used most successfully for this purpose
contain the photoreactive benzophenone moiety at sites tolerant to the
modification. For example, Chorev and coworkers (2) showed that a
PTH-(1-34) analog having the benzophenone functional group
attached to the -amino group of lysine-13 cross-linked to an
eight-amino acid receptor fragment located just amino-terminal of TM1,
and mutation of Arg186 in this
segment prevented the formation of the cross-link (Fig. 2). These
results suggest that the side chains of
Lys13 and
Arg186 come within a few angstroms
of each other (2). In another study by the same group, a
PTH-(1-34) analog containing benzoylphenylalanine (Bpa) in place
of alanine-1 covalently cross-linked to a receptor segment in the
COOH-terminal portion of TM6 containing
Met414 and
Met425, and mutation at
Met425 abolished the cross-link
(11). Interestingly,
Met425 is close to the residues
that were previously shown to determine selectivity for
[Arg2]PTH-(1-34)
(33) (Fig. 2).
A third cross-linking site has been identified by our group using an analog of PTHrP-(1-36) containing Bpa at position 23, in place of the native phenylalanine. In this case, the reactive site was mapped to an 18-amino acid segment at the extreme amino terminus of the receptor (residues 23-40) (72) (Fig. 1). Subsequent alanine-scanning mutagenesis of this region revealed two amino acid residues, Thr33 and Gln37, that contribute functional binding interactions to the (7-34) portion of PTH (72).
So far, there has been good correlation between the mutational analyses performed on the PTH receptors and the cross-linking data. As these parallel studies progress, they should help to refine and constrain the model of the ligand-receptor interaction. Recently, Miller and colleagues (21) showed that a secretin analog containing Bpa at position 22 cross-linked to the distal NH2-terminal region of the secretin receptor, consistent with the findings in the PTH1R. Thus it seems likely that there will be considerable similarity in the ligand interaction models developed for the different class II GPCRs.
A ligand-induced conformational shift in the portion of the receptor containing the seven membrane-spanning helixes and connecting loops is thought to be at the heart of the signal transduction mechanism (25). However, for most GPCRs, this process is still poorly understood. Turner and coworkers (108, 109) found evidence that neighboring polar residues in the second transmembrane helix of the PTH1R and the secretin receptor modulate signaling responsiveness to agonist ligands (108), and the authors also obtained evidence for a role of TM2 in determining ligand selectivity (109). Scanning mutagenesis of the PTH1R identified functionally important segments in each of the three extracellular loops, and point mutational analysis of the third extracellular loop showed that changes at Trp437 and Gln440 impaired binding of PTH-(1-34), but not of PTH-(3-34) (64). Similar defects in PTH-(1-34) binding but not PTH-(3-34) binding occurred with point mutations at Arg233 near the middle of TM2 and at Gln451 in the middle of TM7 (Fig. 2). Such results imply that the membrane-spanning helixes and the connecting extracellular loops form a part of the ligand-binding pocket that recognizes residues 1 and 2 of the ligand. Interestingly, when the mutations at Arg233 and Gln451 were combined, binding of PTH-(1-34) was restored, but cAMP signaling was greatly diminished (34). This result suggests that helix 2 and helix 7 may interact, which is consistent with topological models derived from sequence alignment data (22), and that these interactions play a role in transmembrane signaling. Further insights into the conformational changes involved in the receptor signaling mechanism may come from studies on constitutively active receptors and inverse agonists (see below).
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ROLE OF THE PTH1R IN KIDNEY |
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The mRNA transcript encoding the PTH1R is abundantly expressed in kidney and bone, where it is essential for the regulation of mineral ion homeostasis (65, 106, 111). In kidney, PTH stimulates the reabsorption of calcium in the distal nephron, inhibits the reabsorption of phosphate and bicarbonate in the proximal tubules, and enhances the synthesis of 1,25(OH)2D3 in proximal tubular cells (15, 23, 27, 32, 76). The PTH1R mRNA can be found by in situ hybridization techniques in the convoluted and straight portion of the proximal tubules, in the cortical portion of thick ascending limbs, and in the distal convoluted tubules, which coincides with the previously established sites of renal PTH actions (65).
The PTH1R mRNA is transcribed from at least three distinct promoters that give rise to several splice variants differing in the 5' region (53, 75). In humans, most kidney-specific PTH1R transcripts are derived from a promoter located just upstream of the exon encoding the predicted signal peptide (9). Interestingly, Northern blot analysis has shown that glomerular podocytes express a 4.0-kb transcript instead of the typical 2.4-kb PTH1R mRNA transcript found in most other tissues (65), suggesting the use of a far-upstream promoter; and PTH1R protein has been identified in podocytes by immunohistochemical analysis (3). Although the biological significance of these variations in PTH1R gene expression remains uncertain, the demonstration of PTH binding and PTH-mediated second messenger accumulation in freshly isolated glomeruli and in some podocyte cell lines is consistent with a role for PTH (and/or PTHrP) in glomerular function (74, 96).
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ROLE OF THE PTH1R IN DEVELOPMENT |
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The PTH1R is highly expressed in the prehypertrophic chondrocytes of metaphyseal growth plates (66, 67), and in these cells it mediates the autocrine/paracrine actions of PTHrP. By acting through a complex signaling network involving the hedgehog, Wnt, and BMP family of proteins, PTHrP slows the differentiation of growth plate chondrocytes and prevents them from entering the hypertrophic stage. This action of PTHrP allows the bone to grow and elongate normally (57, 63, 116, 118).
Similar to the expression patterns of PTHrP, the PTH1R mRNA is expressed in a variety of other fetal and adult organs (65, 106, 111), and the biological roles mediated by the receptor in these tissues are beginning to be unraveled. For example, PTHrP and the PTH1R have been shown to regulate branching morphogenesis in the mammary gland (121), and other studies have suggested a role for these proteins in the development of skin, hair, pancreas, and teeth (40, 82, 90, 115, 120, 121).
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PTH1R MUTATIONS ARE THE MOST PLAUSIBLE CAUSE OF TWO RARE GENETIC DISORDERS IN HUMANS |
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Because of the importance of the PTH1R in regulating blood calcium levels and skeletal development, it was predicted that mutations in its gene would be associated with severe abnormalities in mineral ion homeostasis or endochondral bone formation (57, 63, 116). These considerations led to the identification of the underlying molecular defects in two rare genetic disorders.
Three different heterozygous PTH1R mutations have been found in genomic
DNA of patients with Jansen's metaphyseal chondrodysplasia, a rare
autosomal dominant disorder that is characterized by short-limbed dwarfism due to an abnormal regulation of endochondral bone formation, severe PTH- and PTHrP-independent hypercalcemia, and increased bone
turnover (87-89). Each of these mutations was shown to cause constitutive, agonist-independent activation of the receptor. When
expressed in COS-7 cells, human PTH1Rs carrying either
the His223 Arg, the Thr410
Pro, or
the Ile458
Arg mutation
showed five- to eightfold increases in basal intracellular cAMP levels,
in comparison with cells expressing the wild-type receptor. Basal inositol trisphosphate levels were
indistinguishable for cells expressing wild-type or mutant receptors.
Analogs of PTH and PTHrP that had been developed earlier as competitive
antagonists of PTH-(1-34) action, such as
[Leu11,D-Trp12]PTHrP-(7-34),
function as inverse agonists with the constitutively active
PTH1Rs; that is, they dose-dependently reduce cAMP levels in cells expressing the mutant receptors (35). When the human PTH1R
with the His223
Arg
mutation was expressed as a transgene in mice under the control of the
rat
1(II) collagen promoter, the growth plates of the animals showed
a significant deceleration of chondrocyte differentiation (90). This
phenotype was similar to that of mice expressing the PTHrP gene under
the control of the same promoter (118) and was the mirror image of that
found in mice having "knock-out" mutations of either the PTHrP
gene or the PTH1R gene (57, 63). These in vitro and in
vivo findings with mutant constitutively active PTH1Rs provided
a plausible explanation for the skeletal abnormalities
seen in patients with Jansen's disease.
Mutations that impair PTH1R function were recently identified in two
unrelated cases of Blomstrand's chondrodysplasia, a rare autosomal
recessive disorder characterized by early lethality, advanced bone
maturation with accelerated chondrocyte differentiation, and probable
defects in mineral ion homeostasis (14). The skeletal changes seen in
the affected infants are similar to those observed in mice homozygous
for the null allele of the PTHrP or PTH1R gene (58, 63) and are
consistent with the presence of homozygous or compound heterozygous
mutations in the PTH1R gene. The mutation found in the PTH1R gene of
one of the affected infants altered the splicing pattern of the
maternally derived mRNA, such that 11 amino acids (residues
373-383) in TM5 were deleted (50). For still unknown reasons, the
paternal allele was not expressed, resulting in a "null"
phenotype for PTH1R expression. In another case of Blomstrand's
disease that resulted from a consanguineous marriage, a homozygous
point mutation in the PTH1R was found that substituted leucine for the
highly conserved proline-132 in the receptor's amino-terminal domain
(Fig. 2) (56, 123). Both the 11-amino acid deletion and the
Pro132 Leu mutation
impaired binding of PTH and PTHrP and markedly reduced responsiveness
to these ligands in cAMP accumulation assays.
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PSEUDOHYPOPARATHYROIDISM TYPE IB IS NOT CAUSED BY MUTATIONS IN THE PTH1R GENE |
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Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare disorder
characterized by hypocalcemia and hyperphosphatemia, which is caused by
resistance toward PTH. Unlike patients affected by PHP-Ia, which show
reduced activity of the stimulatory G protein due to a variety of
mutations in its gene (GNAS1),
individuals affected by PHP-Ib show no resistance toward other hormones
and no associated developmental abnormalities (68, 114, 117). Because
of this selective resistance toward a single hormone, PHP-Ib was
initially thought to be caused by inactivating mutations in the PTH1R
gene (94, 95). However, such mutations were excluded in a considerable number of PHP-Ib patients for the coding and noncoding exons (10, 29,
91) and at the mRNA level (30, 100). Consistent with the conclusion
that there are no structural abnormalities in the PTH1R, individuals
with PHP-Ib frequently show normal osseous response to PTH or even
biochemical and radiological evidence for increased osteoclastic
resorption, indicating that the PTH-dependent actions on osteoblasts
are not impaired (68, 78, 114). Moreover, PHP-Ib patients typically
show no abnormalities in growth plate development and thus show normal
longitudinal growth, indicating that the PTHrP-dependent regulation of
chondrocyte growth and differentiation is normal. Recently, a
genome-wide search using genomic DNA from numerous affected and
unaffected individuals of four unrelated kindreds led to the
identification of a locus on the telomeric end of chromosome 20q, which
contains at least portions of the
GNAS1 gene. These findings suggest the
possibility that PHP-Ib is caused by a defect in a tissue- or
cell-specific enhancer or promoter of the
GNAS1 gene, or an as yet unidentified gene in the same chromosomal region (54).
In summary, significant progress has been made in understanding the role of the common PTH/PTHrP receptor, the PTH1R, in mammalian biology, particularly with regard to its normal role in chondrocyte growth and development, and its pathological role in two rare genetic disorders in humans. Amino acid residues in the PTH1R and PTH2R that are likely to be important for ligand-receptor interaction and for signal transduction have been identified through mutagenesis methods and through photoaffinity cross-linking techniques. Although these studies have provided new insights into the mode of ligand-receptor interaction, there is still much that needs to be learned about this complex process. Furthermore, it will be important to investigate the biological importance of the PTH2R, to search for novel receptors that may be selective for different portions of PTH or PTHrP, and to identify new peptide ligands that act upon these systems.
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ACKNOWLEDGEMENTS |
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Present address of M. Mannstadt: Medizinische Poliklinik, Ludwig-Maximilliams-Universität, Munich, Germany 80336.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Jüppner, Endocrine Unit, Department of Medicine and Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114. (E-mail: jueppner{at}helix.mgh.harvard.edu).
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