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T B Usdin

Publications and source records attributed to T B Usdin.

At least 19 recordsLinked to original sources
PubMed2006

Forebrain projections of tuberoinfundibular peptide of 39 residues (TIP39)-containing subparafascicular neurons.

Neurons containing tuberoinfundibular peptide of 39 residues (TIP39) constitute a rostro-caudally elongated group of cells in the posterior thalamus. These neurons are located in the rostral part of the subparafascicular nucleus and in the subparafascicular area, caudally. Projections of the caudally located TIP39 neurons have been previously identified by their disappearance following lesions. We have now mapped the projections of the rat rostral subparafascicular neurons using injections of the anterograde tracer biotinylated dextran amine and the retrograde tracer cholera toxin B subunit, and confirmed the projections from more caudal areas previously inferred from lesion studies. Neurons from both the rostral subparafascicular nucleus and the subparafascicular area project to the medial prefrontal, insular, ecto- and perirhinal cortex, nucleus of the diagonal band, septum, central and basomedial amygdaloid nuclei, fundus striati, basal forebrain, midline and intralaminar thalamic nuclei, hypothalamus, subthalamus and the periaqueductal gray. The subparafascicular area projects more densely to the amygdala and the hypothalamus. In contrast, only the rostral part of the subparafascicular nucleus projects significantly to the superficial layers of prefrontal, insular, ectorhinal and somatosensory cortical areas. Double labeling showed that anterogradely labeled fibers from the rostral part of the subparafascicular nucleus contain TIP39 in many forebrain areas, but do not in hypothalamic areas. Injections of the retrograde tracer cholera toxin B subunit into the lateral septum and the fundus striati confirmed that they were indeed target regions of both the rostral subparafascicular nucleus and the subparafascicular area. In contrast, TIP39 neurons did not project to the anterior hypothalamic nucleus. Our data provide an anatomical basis for the potential involvement of rostral subparafascicular neurons in limbic and autonomic regulation, with TIP39 cells being major subparafascicular output neurons projecting to forebrain regions.

Animals↗
PubMed2005

Afferent connections of the subparafascicular area in rat.

The subparafascicular nucleus and the subparafascicular area are the major sites of synthesis of the recently discovered neuropeptide, tuberoinfundibular peptide of 39 residues (TIP39). Better knowledge of the neuronal inputs to the subparafascicular area and nucleus will facilitate investigation of the functions of TIP39. Thus, we have injected the retrograde tracer cholera toxin B subunit into the rostral, middle, and caudal parts of the rat subparafascicular nucleus. We report that the afferent projections to the subparafascicular nucleus and area include the medial prefrontal, insular, and ectorhinal cortex, the subiculum, the lateral septum, the anterior amygdaloid area, the medial amygdaloid nucleus, the caudal paralaminar area of the thalamus, the lateral preoptic area, the anterior, ventromedial, and posterior hypothalamic nuclei, the dorsal premamillary nucleus, the zona incerta and Forel's fields, the periaqueductal gray, the deep layers of the superior colliculus, cortical layers of the inferior colliculus, the cuneiform nucleus, the medial paralemniscal nucleus, and the parabrachial nuclei. Most of these regions project to all parts of the subparafascicular nucleus. However, the magnocellular subparafascicular neurons, which occupy the middle part of the subparafascicular nucleus, may not receive projections from the medial prefrontal and insular cortex, the medial amygdaloid nucleus, the lateral preoptic area, and the parabrachial nuclei. In addition, double labeling of cholera toxin B subunit and TIP39 revealed a remarkable similarity between input regions of the subparafascicular area and the brain TIP39 system. Neurons within regions that contain TIP39 cell bodies as well as regions that contain TIP39 fibers project to the subparafascicular area. Overall, the afferent connections of the subparafascicular nucleus and area suggest its involvement in central reproductive, visceral, nociceptive, and auditory regulation.

Afferent Pathways↗
PubMed2004

Localization and chemical characterization of the audiogenic stress pathway.

Neuronal pathways involved in stress responses to extreme somatosensory stimuli were investigated by immunostaining, viral tract tracing, and experimental brain surgery in rats. Acute audiogenic stress, which elicits an immediate marked elevation in plasma ACTH and corticosterone concentrations, was used as a model. Loud noise (105 dB, 30 min) elicited c-fos activation within neurons in all of the components of the auditory system and stress-sensitive brain nuclei, including corticotropin-releasing hormone-synthesizing parvicellular neurons in the hypothalamic paraventricular nucleus (PVN). c-Fos activation was also seen in the medial paralemniscal nucleus in the pons (MPL) and in the subparafascicular nucleus (SPF) in the midbrain. After injection of neurotropic virus (pseudorabies, Bartha strain) into the PVN, neurons in the MPL and the parvicellular portion of the SPF were retrogradely infected. It has been shown by immunostaining that MPL and SPF neurons express a newly discovered neuropeptide, tuberoinfundibular peptide of 39 residues (TIP39). TIP39 is present in a fine neuronal network in the PVN. Audiogenic stress-elicited c-fos activation in TIP39-containing neurons of the MPL and SPF. TIP39 immunoreactivity disappeared from the PVN after transection of MPL and SPF projections to the nucleus. These observations suggest that TIP39-containing MPL and SPF neurons may participate in mediating audiogenic stress responses.

Animals↗
PubMed2003

Neurons containing tuberoinfundibular peptide of 39 residues project to limbic, endocrine, auditory and spinal areas in rat.

Accumulating evidence suggests that tuberoinfundibular peptide of 39 residues (TIP39) may be the endogenous ligand of the parathyroid hormone 2 receptor. The vast majority of TIP39-containing neurons are localized in two regions, the subparafascicular area at the thalamic-midbrain junction, and the medial paralemniscal nucleus in the rostral pons. In contrast to the restricted localization of TIP39-containing cell bodies, TIP39-containing fibers have a widespread distribution. TIP39 neurons were lesioned electrolytically to determine the origin of TIP39-containing fibers within different parts of the rat CNS. Following bilateral lesions of the medial subparafascicular area including the subparafascicular nucleus, TIP39-immunoreactive fibers almost completely disappeared from forebrain regions including the anterior limbic cortical areas, the shell and cone portions of the nucleus accumbens, the lateral septum, the bed nucleus of the stria terminalis, the amygdaloid nuclei, the fundus striati, the subiculum, the thalamic paraventricular nucleus, and the hypothalamic paraventricular, dorsomedial and arcuate nuclei. Unilateral lesions of the medial and the lateral subparafascicular area demonstrated that the projections are ipsilateral and that medial lesions produce higher reductions in the density of TIP39 fibers except in the amygdala and the hypothalamus. Following lesions of the medial paralemniscal nucleus, TIP39-immunoreactive fibers disappeared from the medial geniculate body, the periaqueductal gray, the deep layers of the superior colliculus, the external cortex of the inferior colliculus, the cuneiform nucleus, the nuclei of the lateral lemniscus, the lateral parabrachial nucleus, the locus coeruleus, the subcoeruleus area, the medial nucleus of the trapezoid body, the periolivary nuclei, and the spinal cord, suggesting that these regions receive TIP39-containing fibers from the medial paralemniscal nucleus, and unilateral lesions demonstrated that the projections are ipsilateral. The projections of the TIP39-containing cells in the subparafascicular area suggest their involvement in limbic and endocrine functions, while the projections of the TIP39-containing cells in the medial paralemniscal nucleus suggest their involvement in auditory and nociceptive functions.

Animals↗
PubMed2002

The parathyroid hormone 2 (PTH2) receptor.

The human PTH2 receptor binds and is activated at high potency by PTH and by the recently discovered peptide tuberoinfundibular peptide of 39 residues (TIP39). Rat and zebrafish PTH2 receptors are more weakly activated by PTH, suggesting that TIP39 may be the natural ligand for the PTH2 receptor. Unlike the PTH1 receptor, the PTH2 receptor interacts extremely weakly with parathyroid hormone-related peptide (PTHrP). The PTH2 receptor is strongly coupled to stimulation of cAMP accumulation, and more weakly, in a cell-specific manner to increases in intracellular calcium concentration. A variety of evidence supports the general model of receptor amino terminal sequences binding ligand carboxyl terminal sequences with high affinity, and ligand amino terminal sequences activating the receptor through interaction with the "juxtamembrane" portion of the receptor. The receptor is present at greatest levels in the nervous system. It is expressed in scattered cells in the cerebral cortex and basal ganglia and at relatively high abundance in the septum, midline thalamic nuclei, several hypothalamic nuclei, and the dorsal horn of the spinal cord. Peripherally, expression in pancreatic islet somatostatin cells is most dramatic. Functional hypotheses based on the receptor's distribution are being tested. Recent data support involvement in hypothalamic releasing-factor secretion and pain.

Amino Acid Sequence↗
PubMed2001

Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors.

The mammalian parathyroid hormone (PTH) / PTH receptor family includes PTH1 and PTH2 receptors and three related ligands (PTH, PTH-related protein (PTHrP) an d tuberoinfundibular peptide of 39 residues (TIP39)). Here we comparatively and systematically review the pharmacological properties of PTH receptors and ligands, structure of the ligands, and molecular mechanisms of receptor-ligand interaction. The PTH1 receptor is activated by PTH and PTHrP but not by TIP39. The PTH2 receptor is activated by TIP39 but not by PTHrP. PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors. Receptor-G-protein interaction increases the receptor binding selectivity of PTHrP and TIP39. Despite different primary structures, the secondary structures of PTH, PTHrP and TIP39 are quite similar. Each ligand contains an N-terminal and a C-terminal alpha-helix in secondary structure-inducing conditions. Receptor-bound ligand structure is less well-characterized. The orientation of receptor-ligand interaction is highly similar for PTH and PTHrP binding to the PTH1 receptor and TIP39 interaction with the PTH2 receptor. Ligands bind according to a 'two-site' mechanism, in which the C-terminal portion of the ligand binds the extracellular N-terminal domain of the receptor (N-interaction), and the N-terminal ligand portion binds to the juxtamembrane receptor domain (J-interaction). The N-interaction provides most of the PTH1-receptor binding energy for PTH and PTHrP but provides less energy for PTH2 receptor-TIP39 interaction. The J-interaction stimulates G-protein activation. For the PTH-PTH1 receptor interaction, the efficacy-generating component of the J-interaction is independent of the N-domain of the receptor and C-terminal portion of the ligand. This finding suggests that it might be possible to design low molecular-weight PTH1 receptor agonists, which could be bone anabolic agents and used for the treatment of osteoporosis.

Amino Acid Sequence↗
PubMed2001

Regions in rat and human parathyroid hormone (PTH) 2 receptors controlling receptor interaction with PTH and with antagonist ligands.

The parathyroid hormone (PTH) 2 receptor is potently activated by tuberoinfundibular peptide (TIP39). Rat and human PTH2 receptors differ considerably in their PTH responsiveness. PTH weakly stimulates cAMP accumulation via the rat receptor, and here we show it did not detectably increase intracellular calcium ([Ca2+]i) and bound with low affinity (450 nM). For the human PTH2 receptor PTH was a full agonist for increasing cAMP, a partial agonist for increasing [Ca2+]i, and bound with high affinity (18 nM). In addition, the antagonists PTH(7-34) and TIP(7-39) bound with 10- to 49-fold lower affinity to the rat receptor. We investigated the molecular basis of differential PTH and antagonist interaction with human and rat PTH2 receptors by using chimeric human/rat PTH2 receptors. PTH cAMP-signaling efficacy (Emax) was determined by extracellular loop (EL) 1 and a region including EL2 and EL3. The N-terminal domain determined PTH binding selectivity at the inactive receptor state. Multiple regions throughout the receptor are required for the PTH-PTH2 receptor complex to adopt a high-affinity active state: inserting the rat receptor's N-terminal domain, EL1 or EL2/3, into the human receptor increased PTH's EC50 and reciprocal exchanges did not reduce EC50. This suggests the global receptor conformation prevents the rat receptor from adopting a high-affinity state when in complex with PTH. N-terminal ligand truncation, producing the antagonists PTH(7-34) and TIP(7-39), altered ligand interaction with the membrane-embedded domain of the receptor, eliminating EL2/3 as a specificity determinant and lowering binding affinity. These insights should contribute to the development of a high-affinity PTH2 receptor antagonist, for investigating the receptor's physiological role.

Algorithms↗
PubMed2000

Evaluating the signal transduction mechanism of the parathyroid hormone 1 receptor. Effect of receptor-G-protein interaction on the ligand binding mechanism and receptor conformation.

Ligand binding to the PTH1 receptor is described by a "two-site" model, in which the C-terminal portion of the ligand interacts with the N-terminal domain of the receptor (N interaction), and the N-terminal region of the ligand binds the juxtamembrane domain of the receptor (J interaction). Previous studies have not considered the dynamic nature of receptor conformation in ligand binding and receptor activation. In this study the ligand binding mechanism was compared for the G-protein-coupled (RG) and uncoupled (R) PTH1 receptor conformations. The two-site model was confirmed by demonstration of spatially distinct binding sites for PTH(3-34) and PTH(1-14): PTH(1-14), which binds predominantly to the J domain, only partially inhibited binding of 125I-PTH(3-34); and PTH(3-34), shown to bind predominantly to the N domain, only partially inhibited PTH(1-14)-stimulated cAMP accumulation. To assess the effect of R-G coupling, ligand binding to R was measured by displacement of 125I-PTH(3-34) with 30 microM guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) present, and binding to RG was measured by displacement of 125I-[MAP]PTHrP(1-36) (where MAP is model amphipathic peptide), a new radioligand that binds selectively to RG. Agonists bound with higher affinity to RG than R, whereas antagonists bound similarly to these states. The J interaction was responsible for enhanced agonist binding to RG: residues 1 and 2 were required for increased PTH(1-34) affinity for RG; residue 5 of MAP-PTHrP(1-36) was a determinant of R/RG binding selectivity, and PTH(1-14) bound selectively to RG. The N interaction was insensitive to R-G coupling; PTH(3-34) binding was GTPgammaS-insensitive. Finally, several observations suggest the receptor conformation is more "closed" at RG than R. At the R state, an open conformation is suggested by the simultaneous binding of PTH(1-14) and PTH(3-34). At RG PTH(1-14) better occluded binding of 125I-PTH(3-34) and agonist ligands bound pseudo-irreversibly, suggesting a more closed conformation of this receptor state. The results extend the two-site model to take into account R and RG conformations and suggest a model for differences of receptor conformation between these states.

Cells, Cultured↗
PubMed2000

Molecular determinants of tuberoinfundibular peptide of 39 residues (TIP39) selectivity for the parathyroid hormone-2 (PTH2) receptor. N-terminal truncation of TIP39 reverses PTH2 receptor/PTH1 receptor binding selectivity.

Tuberoinfundibular peptide of 39 residues (TIP39) and the parathyroid hormone-2 (PTH2) receptor form part of an extended family of related signaling molecules that includes the PTH1 receptor, which responds to PTH and PTH-related protein. TIP39 does not appreciably activate the PTH1 receptor, but in this study it is shown to bind the receptor with moderate affinity (59 nm). In this study, we investigated the molecular determinants of both ligand and receptor for the PTH2 receptor selectivity of TIP39 and quantitatively evaluated the role of molecular elements in the binding of TIP39 to the PTH2 and PTH1 receptors. A chimeric receptor composed of the N-terminal extracellular domain of the PTH1 receptor and the remainder (juxtamembrane domain) of the PTH2 receptor (P2-NP1) was fully activated by TIP39 (E(max) = 98% of the rPTH-(1-34), E(max), EC(50) = 2.0 nm). This receptor chimera bound TIP39 with an equivalent affinity to the wild-type PTH2 receptor (2. 3 and 2.0 nm, respectively). The reciprocal chimeric receptor (P1-NP2) was not activated by TIP39 and bound the ligand with an affinity equivalent to that of the PTH1 receptor. Thus, the juxtamembrane receptor domain specifies the signaling and binding selectivity of TIP39 for the PTH2 receptor over the PTH1 receptor. Removing six N-terminal residues of TIP39 eliminated activation of the PTH2 receptor and reduced binding affinity 70-fold. In contrast, this truncation increased affinity for the PTH1 receptor 10-fold, reversing the PTH2/PTH1 receptor binding selectivity and resulting in a high affinity interaction of TIP-(7-39) with the PTH1 receptor (6 nm). These findings can be explained by a strong interaction between the N-terminal region of TIP39 and the juxtamembrane domain of the PTH2 receptor, with the corresponding domain of the PTH1 receptor acting as a selectivity barrier against high affinity binding of TIP39. As a result, TIP-(7-39) is a highly potent, selective antagonist for the PTH1 receptor.

Amino Acid Sequence↗
PubMed2000

New members of the parathyroid hormone/parathyroid hormone receptor family: the parathyroid hormone 2 receptor and tuberoinfundibular peptide of 39 residues.

The parathyroid hormone (PTH) family currently includes three peptides and three receptors. PTH regulates calcium homeostasis through bone and kidney PTH1 receptors. PTH-related peptide, probably also through PTH1 receptors, regulates skeletal, pancreatic, epidermal, and mammary gland differentiation and bladder and vascular smooth muscle relaxation and has a CNS role that is under investigation. Tuberoinfundibular peptide of 39 residues (TIP39) was recently purified from bovine hypothalamus based on selective PTH2 receptor activation. PTH2 receptor expression is greatest in the CNS, where it is concentrated in limbic, hypothalamic, and sensory areas, especially hypothalamic periventricular neurons, nerve terminals in the median eminence, superficial layers of the spinal cord dorsal horn, and the caudal part of the sensory trigeminal nucleus. It is also present in a number of endocrine cells. Thus TIP39 and PTH2 receptor-influenced functions may range from pituitary and pancreatic hormone release to pain perception. A third PTH-recognizing receptor has been found in zebrafish.

Amino Acid Sequence↗
PubMed2000

Distribution of parathyroid hormone-2 receptor-like immunoreactivity and messenger RNA in the rat nervous system.

The parathyroid hormone-2 receptor is a member of the secretin family of guanine nucleotide-binding protein-coupled receptors. The human parathyroid hormone-2 receptor is activated by parathyroid hormone and a recently purified hypothalamic polypeptide, tubero-infundibular peptide of 39 residues, while the rat parathyroid hormone-2 receptor is poorly activated by parathyroid hormone and is potently activated by tubero-infundibular peptide of 39 residues. In order to provide a foundation for studies on the physiological role of the parathyroid hormone-2 receptor and tubero-infundibular peptide of 39 residues, we investigated the cellular distribution of the parathyroid hormone-2 receptor in the rat CNS using both immunohistochemistry and in situ hybridization histochemistry. The receptor is found in discrete groups of neurons in many regions. It is present in scattered small cells throughout the cerebral cortex, in small and medium-sized cells in the striatum, and is quite abundant in the septum and the midline thalamic nuclei. Its expression is high in the hypothalamus, particularly in the periventricular and arcuate nuclei. Fibers and terminals in the external zone of the median eminence, and in the superficial layers of the caudal spinal trigeminal tract and the spinal cord dorsal horn, are strongly and dramatically labeled by a parathyroid hormone-2 receptor-selective antibody. The localization of parathyroid hormone-2 receptor suggests a role in the regulation of pituitary hormone secretion, sensory information processing and homeostatic regulation.

Animals↗
PubMed2000

Evaluating the ligand specificity of zebrafish parathyroid hormone (PTH) receptors: comparison of PTH, PTH-related protein, and tuberoinfundibular peptide of 39 residues.

Homologs of mammalian PTH1 and PTH2 receptors, and a novel PTH3 receptor have been identified in zebrafish (zPTH1, zPTH2, and zPTH3). zPTH1 receptor ligand specificity is similar to that of mammalian PTH1 receptors. The zPTH2 receptor is selective for PTH over PTH-related protein (PTHrP); however, PTH produces only modest cAMP accumulation. A PTH2 receptor-selective peptide, tuberoinfundibular peptide of 39 residues (TIP39), has recently been purified from bovine hypothalamus. The effect of TIP39 has not previously been examined on zebrafish receptors. The zPTH3 receptor was initially described as PTHrP selective based on comparison with the effects of human PTH. We have now examined the ligand specificity of the zebrafish PTH-recognizing receptors expressed in COS-7 cells using a wide range of ligands. TIP39 is a potent agonist for stimulation of cAMP accumulation at two putative splice variants of the zPTH2 receptor (EC50, 2.6 and 5.2 nM); in comparison, PTH is a partial agonist [maximal effect (Emax) of PTH peptides ranges from 28-49% of the TIP39 Emax]. As TIP39 is much more efficacious than any known PTH-like peptide, a homolog of TIP39 may be the zPTH2 receptor's endogenous ligand. At the zPTH3 receptor, rat PTH-(1-34) and rat PTH-(1-84) (EC50, 0.22 and 0.45 nM) are more potent than PTHrP (EC50, 1.5 nM), and rPTH-(1-34) binds with high affinity (3.2 nM). PTH has not been isolated from fish. PTHrP-like peptides, which have been identified in fish, may be the natural ligands for zPTH1 and zPTH3 receptors.

Animals↗
PubMed2000

Pseudohypoparathyroidism 1b: exclusion of parathyroid hormone and its receptors as candidate disease genes.

Pseudohypoparathyroidism 1b (PHP 1b) is characterized by specific resistance of target tissues to PTH, but no mutations in the PTH/PTH-related peptide (PTHrP) receptor gene have been identified. To investigate the basis for defective PTH signaling, we used polymorphic markers in or near the genes encoding PTH and its receptors to perform linkage analysis between these loci and PHP 1b. Two multiplex PHP 1b families (families M and K) were informative for an intragenic polymorphism in exon 13 of the PTH/PTHrP receptor gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. Linkage analysis revealed discordance of the PTH/PTHrP receptor with PHP1b. One PHP 1b kindred (family M) was informative for a intragenic polymorphism in exon 3 of the PTH gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. The PTH gene polymorphism segregation was discordant with PHP 1b. Probands from each family had normal PTH genes by direct sequence analysis. In three PHP 1b kindreds, we analyzed simple sequence polymorphisms in three microsatellite markers flanking the PTH type 2 receptor locus located at 2q33. Linkage analysis demonstrated no linkage. In conclusion, neither the PTH gene nor the PTH receptor genes (type 1 and 2) are linked to PHP 1b.

Chromosome Mapping↗
PubMed2000

Tuberoinfundibular peptide (7-39) [TIP(7-39)], a novel, selective, high-affinity antagonist for the parathyroid hormone-1 receptor with no detectable agonist activity.

The parathyroid hormone (PTH)-1 receptor mediates the pathophysiological effects of PTH in hyperparathyroidism and PTH-related protein (PTHrP) in humoral hypercalcemia of malignancy. A PTH1 receptor antagonist may be of therapeutic utility in these disorders. We recently identified a novel antagonist, tuberoinfundibular peptide (7-39) [TIP(7-39)], derived from the likely endogenous ligand for the PTH2 receptor TIP39. In this study its in vitro profile is evaluated and compared with that of [D-Trp(12),Tyr(34)]bPTH(7-34) and PTHrP(7-34), representing the two previously known structural classes of PTH1 receptor antagonists. TIP(7-39) binds with higher affinity (6.2 nM) to the PTH1 receptor than [D-Trp(12),Tyr(34)]bPTH(7-34) (45 nM) and PTHrP(7-34) (65 nM) and displays a 5.5-fold greater PTH1/PTH2 receptor selectivity. TIP(7-39) does not stimulate cAMP accumulation via the PTH1 receptor [in a sensitive assay that detects the activity of the weak partial agonist [Nle(8,18),Tyr(34)]bPTH(3-34)] and does not increase intracellular calcium. Schild analysis for TIP(7-39) was consistent with purely competitive antagonism of PTH(1-34)'s stimulation of cAMP accumulation (slope = 0.99 +/- 0.24). The pK(B) for TIP(7-39) (7.1 +/- 0.3) was higher than that for [D-Trp(12),Tyr(34)]bPTH(7-34) (6.5 +/- 0.0) and PTHrP(7-34) (6.0 +/- 0.1). Binding of (125)I-TIP(7-39) to the PTH1 receptor could be measured (K(D) = 1.3 +/- 0.1 nM, B(max) = 1.3 +/- 0.1 pmol/mg), whereas binding of (125)I-[Nle(8,18),D-Trp(12),Tyr(34)]bPTH(7-34) could not be detected. Kinetic analysis indicated that (125)I-TIP(7-39) dissociates much more slowly (t(1/2) = 14 min) than [D-Trp(12),Tyr(34)]bPTH(7-34) (13 s) and PTHrP(7-34) (9 s). The novel antagonist TIP(7-39) therefore displays a more favorable in vitro pharmacological profile than antagonists derived from PTH and PTHrP and may be useful for demonstrating the utility of PTH1 receptor antagonism in the treatment of hypercalcemia.

Animals↗
PubMed1999

Comparison of rat and human parathyroid hormone 2 (PTH2) receptor activation: PTH is a low potency partial agonist at the rat PTH2 receptor.

The human PTH2 receptor, expressed in tissue culture cells, is selectively activated by PTH. Detailed investigation of its anatomical and cellular distribution has been performed in the rat. It is expressed by neurons in a number of brain nuclei; by endocrine cells that include pancreatic islet somatostatin cells, thyroid parafollicular cells, and peptide secreting cells in the gastrointestinal tract; and by cells in the vasculature and heart. The physiological role of the PTH2 receptor expressed by these cells remains to be determined. All pharmacological studies performed to date have used the human receptor. We have now isolated a complementary DNA including the entire coding sequence of the rat PTH2 receptor and compared its pharmacological profile with that of the human PTH2 receptor when each is expressed in COS-7 cells. PTH-based peptides, including rat PTH(1-84), rat PTH(1-34), and human PTH(1-34), have low potency at the rat PTH2 receptor for stimulation of adenylyl cyclase (EC50 = 19-140 nM). When compared with the effect of a bovine hypothalamic extract, PTH-based peptides are partial agonists at the rat PTH2 receptor. This suggests that PTH is unlikely to be a physiologically important endogenous ligand for the PTH2 receptor. A peptide homologous to an activity detected in a bovine hypothalamic extract is a good candidate for the endogenous PTH2 receptor ligand.

Amino Acid Sequence↗