The Experts below are selected from a list of 39 Experts worldwide ranked by ideXlab platform

Harald Jüppner - One of the best experts on this subject based on the ideXlab platform.

  • Receptors for parathyroid hormone and parathyroid hormone related peptide exploration of their biological importance
    Bone, 1999
    Co-Authors: Harald Jüppner
    Abstract:

    The molecular cloning of the PTH/PTHrP Receptor (also termed PTH1 Receptor; PTH1R) and the Receptors for calcitonin and Secretin established a distinct Family of G protein-coupled Receptors. These Receptors are characterized by seven membranespanning domains, a long amino-terminal extracellular domain, and a long carboxyl-terminal intracellular tail, and all members of this Receptor Family share about 45 strictly conserved amino acid residues that are located largely in the membrane-embedded core region of the Receptor and in the extracellular region. The ligands for this group of Receptors are intermediate in length, typically comprising 30–40 residues, and most members of this Receptor Family were shown to signal through at least two distinct signaling pathways: adenylate cyclase/protein kinase A and phospholipase C/protein kinase C. Most cDNAs encoding members of the PTH/calcitonin/Secretin Receptor Family have been isolated thus far from mammalian species. However, some Receptor cDNAs have been obtained from frogs (Xenopus laevis), fishes (Carassius auratus), nematodes (C. elegans), and insects (Manduca sexta and Drosophila), implying that these proteins were present at least 500 million years ago. To date, cDNAs encoding functional PTH1Rs have been isolated from five different mammalian species and a partial clone was isolated from chicken, and cDNAs encoding two different nonallelic Receptor isoforms were isolated from X. laevis. The recently identified PTH2-Receptor (PTH2R), which has unique functional characteristics (see below), shares higher amino acid sequence homology with the PTH1R than with any other member of the Receptor Family, and although its biological role remains to be established, it has proven to be extremely useful for exploring Receptor domains that are important for ligand interaction. Interestingly, different cDNAs that encode three distinct Receptors for PTH and/or PTHrP were recently isolated from zebrafish (Danio rerio). While two of these Receptors are the fish homologs of the mammalian PTH1R and PTH2R, respectively, the third cDNA encodes an entirely novel Receptor, currently termed PTH3R, which has unique functional properties. Since fishes do not have parathyroid glands, and furthermore have different environmental challenges with regard to calcium and phosphate homeostasis as compared with most terrestrial animals, it appears likely that the ancestrial precursor of the PTH/PTHrP Receptor acquired distinct biological functions during vertebrate evolution.

  • inverse agonism of amino terminally truncated parathyroid hormone pth and pth related peptide pthrp analogs revealed with constitutively active mutant pth pthrp Receptors
    Endocrinology, 1996
    Co-Authors: Thomas J. Gardella, Michael D. Luck, Geoffrey S. Jensen, Ernestina Schipani, John T. Potts, Harald Jüppner
    Abstract:

    Inverse agonists, ligands that suppress spontaneous Receptor signaling activity, have been described for a growing number of G protein-coupled Receptors; however, none have been reported for the PTH/calcitonin/Secretin Receptor Family. We took advantage of the constitutive signaling activity of two mutant forms of the PTH/PTH-related peptide (PTHrP) Receptor, recently identified in patients with Jansen's metaphyseal chondrodysplasia, to screen for PTH and PTHrP analogs with inverse agonist activity. Two antagonist peptides, [Leu11, D-Trp12]hPTHrP(7-34)NH2 and [D-Trp12, Tyr34]bPTH-(7-34)NH2, displayed inverse agonist activity and reduced cAMP in COS-7 cells expressing either mutant Receptor by 30-50% (EC50 approximately 50 nM). These data demonstrate that the concept of inverse agonism can be extended to this distinct Family of G protein-coupled Receptors and their cognate antagonist peptide ligands. Such ligands shall be useful probes of the multi-state conformational equilibria proposed for these Receptors and could lead to new approaches for treating human diseases caused by Receptor activating mutations.

Dan Donnelly - One of the best experts on this subject based on the ideXlab platform.

  • The arrangement of the transmembrane helices in the Secretin Receptor Family of G-protein-coupled Receptors
    FEBS letters, 1997
    Co-Authors: Dan Donnelly
    Abstract:

    The members of the Secretin Receptor Family of G-protein-coupled Receptors share no significant sequence similarity to the more familiar rhodopsin-like Family. However, multiple sequence alignment analysis reveals seven hydrophobic regions with significant α-helical periodicity. Residues that are likely to be buried on the interior of the helical bundle and others that are likely to contact the lipid bilayer are identified. A predicted arrangement of the helical bundle is described in which, by comparison with the arrangement in the rhodopsin Family, helices 2 and 7 are more buried within the bundle while helix 3 is more exposed to the lipid bilayer.

Shigehisa Hirose - One of the best experts on this subject based on the ideXlab platform.

  • ig hepta a novel member of the g protein coupled hepta helical Receptor gpcr Family that has immunoglobulin like repeats in a long n terminal extracellular domain and defines a new subFamily of gpcrs
    Journal of Biological Chemistry, 1999
    Co-Authors: Junpei Abe, Hiroyuki Suzuki, Michitaka Notoya, Tadashi Yamamoto, Shigehisa Hirose
    Abstract:

    A novel member of the G protein-coupled Receptor (GPCR) Family was cloned and characterized, which is unique, among the members, in its long extracellular domain comprising Ig-like repeats and in its high expression predominantly in the lung. The clone (Ig-Hepta) was first identified as a polymerase chain reaction product generated with primers designed to amplify Secretin Receptor Family members including the parathyroid hormone-related peptide Receptors. Analysis of the open reading frame of cDNAs isolated from a rat lung cDNA library indicated that Ig-Hepta is a protein of 1389 amino acid residues and has two Ig-like repeats in the N-terminal extracellular domain (exodomain) of 1053 amino acid residues and 7 transmembrane spans in the C-terminal region. Northern blot analysis revealed very high expression of its mRNA in the lung and low but detectable levels in the kidney and heart. The mRNA expression in the lung was found to be strongly induced postnatally. Biochemical analysis indicated that Ig-Hepta is a highly glycosylated protein and exists as a disulfide-linked dimer. Immunohistochemistry on rat lung and kidney sections revealed dense localization of Ig-Hepta in alveolar walls and intercalated cells in the collecting duct, respectively, suggesting a role in the regulation of acid-base balance. Ig-Hepta defines a new subFamily of GPCRs.

Laurence J Miller - One of the best experts on this subject based on the ideXlab platform.

  • Secretin and vasoactive intestinal peptide Receptors members of a unique Family of g protein coupled Receptors
    Gastroenterology, 1998
    Co-Authors: Charles D Ulrich, Martin H Holtmann, Laurence J Miller
    Abstract:

    The superFamily of guanine nucleotide–binding protein (G protein)-coupled Receptors represents the largest group of Receptor molecules yet identified. They bind ligands as structurally diverse as photons, odorants, biogenic amines, peptides, and large glycoproteins. This entire spectrum of natural agonists is accommodated by members of the largest, most extensively studied, and best understood Family of such Receptors, the rhodopsin/ b-adrenergic Receptor Family. Recently, another distinct Family within this superFamily was identified.1 Known as the Secretin Receptor Family, this Family shares few of the specific sequence motifs of the rhodopsin/b-adrenergic Receptor Family and has less than 12% sequence homology with it, but still possesses the same predicted molecular architecture with seven transmembrane helices and appears to signal via a similar sequence of molecular events (Figure 1).1 Among the members of this Family are Receptors for two extremely important regulators of pancreatic, biliary, and gastrointestinal physiology: Secretin and vasoactive intestinal polypeptide (VIP). Because of their clear physiological relevance to gastroenterology, they are the focus of this review. Also included in the Secretin Receptor Family are Receptors for pituitary adenylate cyclase–activating polypeptide (PACAP),2 gastric inhibitory polypeptide (GIP),3 glucagon,4 glucagon-like peptide 1,5 calcitonin,6 calcitonin gene-related peptide,7 parathyroid hormone,8 growth hormone–releasing factor (GHRF),9 corticotropin-releasing factor,10 insect diuretic hormone,11 and a few orphan Receptors or more distantly related molecules. These Receptors share substantial homology with each other, and all bind moderately large peptides possessing diffuse pharmacophoric domains. Some of these Receptors are probably important in digestive physiology, but our current understanding of them does not suggest the presence of unique themes distinct from those that are developed in the following discussion. Biochemical and Molecular Characterization of Gastrointestinal Hormone Receptors

Jeff D. Reagan - One of the best experts on this subject based on the ideXlab platform.

  • expression cloning of an insect diuretic hormone Receptor a member of the calcitonin Secretin Receptor Family
    Journal of Biological Chemistry, 1994
    Co-Authors: Jeff D. Reagan
    Abstract:

    Abstract Insect diuretic hormones and their Receptors regulate fluid and ion secretion and thus are attractive targets for the design of novel insect control agents. A complementary DNA clone encoding a corticotropin-releasing factor-related diuretic hormone Receptor from the tobacco hornworm Manduca sexta was isolated by expression cloning in COS-7 cells. The Receptor consists of 395 amino acids and contains seven putative transmembrane domains. The expressed Receptor binds M. sexta diuretic hormone, as well as several related insect diuretic peptides with high affinity. Furthermore, each of these peptides stimulate adenylate cyclase in COS-7 cells transfected with the Receptor. The M. sexta diuretic hormone Receptor is homologous to the Receptors for calcitonin, Secretin, vasoactive intestinal peptide, parathyroid hormone, glucagon-like peptide 1, growth hormone-releasing hormone, pituitary adenylate cyclase-activating polypeptide, and glucagon. The M. sexta diuretic hormone Receptor is the first nonmammalian member of this Family to be identified.