General

Parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), and tuberoinfundibular peptide of thirty-nine residues (TIP39) are endogenous ligands for the parathyroid hormone type 1 and 2 parathyroid hormone receptors. PTH is a classic endocrine hormone essential for mineral homeostasis [43]. It is synthesized as a pre-pro-protein by chief cells of the parathyroid gland. Its secretion is regulated by plasma calcium levels via a calcium-sensing receptor, a G protein-coupled receptor (GPCR). Mature PTH is an 84 residue polypeptide. Most of the characterized effects of PTH can be brought about by the first 34 N-terminal residues of this polypeptide, and PTH(1-34) that is the most commonly used receptor ligand.

PTHrP is the product of a distinct gene [18,41,49]. It has about 70% sequence identity with PTH over the first 34 N-terminal residues that interact with the receptor transmembrane domains and extracellular loops. The effects of exogenous PTHrP are indistinguishable from those of PTH. PTHrP was originally identified as humoral hypercalcemia of malignancy factor, an activity secreted by a number of different tumors. It is now known to be a widely distributed paracrine factor, and has been shown to play a role in the development and remodeling of many tissues, in transepithelial calcium transport, and in smooth muscle relaxation.

TIP39 shares four amino acid identities with both PTH and PTHrP, and six with PTH [54]. Many more of its residues share similar charge or hydrophobicity and it has a similar conformation [42]. It was purified from bovine hypothalamus on the basis of its activation of the parathyroid hormone 2 (PTH2) receptor ([53]; see below). Its physiological role(s) remain to be established. Some evidence supports its involvement in regulation of nociception, hypothalamic, and anxiety-related functions [11,51].

Receptors

A common receptor for PTH and PTHrP is referred to as the PTH/PTHrP or PTH1 receptor. It was originally cloned from opossum kidney [30] and bone tumor cell lines [1]. It is a member of Family B GPCRs. PTH and PTHrP have virtually indistinguishable interactions with the cloned PTH1 receptor, when using traditional bioassays performed under equilibrium conditions, including high affinity binding and stimulation of cAMP and cytoplasmic calcium accumulation in cells transfected with the receptor [16]. Evidence supports coupling to both G_s and G_q G-proteins [39]. PTH1 receptor signaling via G_s or G_q is regulated in a cell- and ligand-specific manner by β-arrestins [20,57,60]] and the PDZ protein NHERF1 [33,59]. PTH1 receptor expression is particularly high in skeletal tissues and kidney but it has a nearly ubiquitous tissue distribution.

The PTH2 receptor was identified in a sequence based screen for novel Family B GPCRs present in brain-derived cDNA libraries [52]. It has about 50% sequence identity with the PTH1 receptor. It is most abundant in brain and testes, and low levels have been reported in a number of other tissues [50]. The human PTH2 receptor is potently activated by PTH. Failure by one group of investigators to detect PTH synthesis in the brain, and poor activation of the rat PTH2 receptor by PTH, lead to the discovery of TIP39 [53]. TIP39 is a high affinity, potent agonist at both the human and rat PTH2 receptors. It has low affinity and negligible agonism at PTH1 receptors. An excellent match between the neuroanatomical distributions of TIP39 and the PTH2 receptor supports the identification of TIP39 as the endogenous ligand of the PTH2 receptor [10].

Additional receptors for PTHrP, PTH and specific fragments of these proteins have been proposed by a number of investigators based on effects that do not appear to be explained by the currently known receptors [37], but so far no other additional molecularly distinct receptors have been identified in mammals.

There is an extensive body of work aimed at defining the functions of particular domains and residues within the PTH1 receptor, reviewed in [18,58]. A PTH1 receptor isoform lacking the 7th transmembrane domain and that acts as a dominant-negative to suppress wild-type receptor trafficking has been identified and may account for some forms of PTH resistance [2]. Some of this work takes advantage of the partially overlapping ligand selectivity of the PTH1 and PTH2 receptors to define features that contribute to their specificity.

Receptor-ligand interaction

Most pharmacological investigation of PTH receptors uses modified endogenous peptide ligands. Peptides containing the first 34 N-terminal residues of PTH or first 36 of PTHrP are commonly used, and several substitutions have been introduced to increase the peptides stability or to facilitate radioiodination. Residues within the amino terminus of PTH and PTHrP contribute relatively little to the affinity of receptor binding but are essential for receptor activation [46]. Amino-terminal PTH fragment analogs containing affinity-enhancing substitutions in the N-terminal region exhibit high potency on the PTH1 receptor [40,47-48]. PTH/PTHrP hybrids and conformationally constrained cyclic PTH and PTHrP analogs were critical in understanding SAR and bioactive conformation [3-4,34,36]. Peptides lacking several of the amino terminal residues are used as antagonists [12,38]. Removing amino terminal residues from TIP39 decreased its potency as a PTH2 receptor agonist, but deleting enough residues to remove all detectable agonism greatly reduced its affinity for the PTH2 receptor [21]. In contrast, removing amino terminal residues increased the affinity of TIP39 for the PTH1 receptor, and a TIP39 analog lacking amino terminal residues is a potent PTH1 receptor antagonist [26]. A TIP39 analog with four amino acid substitutions near the N-terminal is a PTH2 receptor antagonist with very low affinity for the PTH1 receptor [32].

Only a few small molecule ligands have been reported for the PTH1 receptor, and most of these are low affinity antagonists, although some antagonists have been developed with near-nanomolar affinities [35]. The compound SW106 is a micromolar antagonist that competitively inhibits the binding of a modified M-PTH(1-14) analog, and thus binds to the transmembrane domain/extracellular loop region of the receptor [5]. Compound AH-3960 is the only small molecule compound that exhibits agonist activity on the PTH1 receptor, albeit potency is in the low micromolar range [35].

Almost all studies of ligand binding to PTH receptors have been performed with intact cells. One set of studies has described use of membrane preparations and evaluation of different G-protein interacting states [22-25,27]. Amino-terminally modified PTH(1-34) and PTH(1-28) analogs that exhibit high affinity for the PTHR1 even in the presence of GTPγS, are thought to bind to a novel G protein-independent conformation, called R⁰ [8,40]. The stable binding of these analogs to the receptor is paralleled by prolonged cAMP signaling responses in cells, and prolonged calcemic and phosphaturic responses in mice [14-15,40]. Förster resonance energy transfer (FRET)-based approaches have been used to measure in real time in live cells kinetics of biochemical reactions involved in the signaling cascade of PTHR. These kinetics revealed ligand–receptor interaction mechanisms and rate-limiting reactions engaged in activation of PTHR and its cognate G_S protein [6,15].

A new mechanism of signal transduction for the PTH1R

It has been generally assumed that the production of cAMP mediated by GPCR and termination of signaling take place exclusively at the plasma membrane. Recent studies reveal that the PTH1 receptor does not always follow this conventional paradigm. In the new model, PTH and high-affinity conformation (R⁰) selective PTH analogs trigger cAMP production not only from the plasma membrane, but also from endosomal membranes [15,55]. This new model proposes that internalization of cell surface ligand-PTH1 receptor complexes into early endosomes maintains cAMP production for an extended period of time. This model is now widely appreciated to be a new component to GPCR signal transduction [56]. Parts of the molecular and cellular mechanisms of this unexpected process have been determined in the case of the PTH1 receptor [14,17,19,60] but the physiological consequences of this model for human biology remain undetermined.

Disease association

Because of its critical role in regulation of calcium metabolism and bone growth and remodeling the PTH1 receptor is of great interest in the treatment of osteoporosis [44]. This PTH1 receptor is also relevant to hypoparathyroidism, and several genetic diseases have been demonstrated to result from its mutants. Blomstrand's lethal chondrodysplasia results from inactivating mutations in the PTH1 receptor [29,31]. Mutations in the PTH1 receptor that lead to increased constituitive activity cause Jansen's metaphyseal chondrodysplasia [45], a disease in which abnormal growth plate organization leads to short stature via shortening of the long bones. Furthermore, PTH1 receptor mutations have been found in patients with Eiken’s disease [13], in some patients with Ollier’s disease [7,28], and in patients with autosomal dominant, isolated primary failure of tooth eruption [9,61].

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