Hartmut Glossmann

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Hartmut Glossmann (born November 3, 1940 in Kassel ) is a German doctor , pharmacologist with additional training in clinical pharmacology and emeritus full professor for biochemical pharmacology at the Medical University of Innsbruck . He is the successor to Heribert Konzett in his (renamed Biochemical Pharmacology) Chair of Pharmacology and founder of the Institute for Biochemical Pharmacology. He is known for his work in the field of voltage-dependent calcium channels of the plasma membrane . In his institute, among other things were Sigma-1 receptor first isolated, cloned and expressed biochemically and enzymes of Postsqualen- biosynthesis (Delta 7-dehydrocholesterol reductase , DHCR 7, sterol - isomerase , identical with emopamil binding protein , EPB ) characterized. In cooperation with the Innsbruck human geneticist Gerd Utermann , the molecular causes of the Smith-Lemli-Opitz syndrome (SLO) and, in international cooperation, the Conradi-Hünermann syndrome were clarified.

Life

Hartmut Glossmann was born in Kassel in 1940. He studied medicine at the Justus Liebig University in Giessen , where he received his doctorate in 1966. His doctoral thesis in the field of biochemical pharmacology (with Maximilian Frimmer habilitand of Manfred Kiese ) was honored in 1968 with the prize of the University of Giessen for the best doctoral thesis. After training as a medical practitioner, including country doctor practice, internal medicine, gynecology, surgery and pharmacology, joined Glos man after his license to practice medicine in 1968 as a fellow of the German Research Foundation at the Max Planck Institute of Biochemistry (Director: Adolf Butenandt ) and the Max -Planck Institute for Protein and Leather Research (Working groups: Jürgen Engel and Robert Huber ) in Munich and learned protein chemistry and optical methods for determining the structure of proteins. This was followed by a three-year research stay in the USA as a visiting scientist at the National Institute of Health in Bethesda / Maryland (David M. Neville jr. And Kevin J. Catt). After his return to Germany, he received his habilitation in pharmacology in 1975 and the following year he was appointed C2 professor at the Rudolf Buchheim Institute for Pharmacology in Giessen under Ernst Habermann . In the same year, Glossmann acquired the title of specialist in pharmacology and toxicology, and in 1984 the title of specialist in clinical pharmacology. In March 1984 he became a full professor at the Medical Faculty of the University of Innsbruck and successor to the chair of Heribert Konzett. In 1989 Glossmann received a visiting professor of pharmacology and cell physiology at the University of Cincinnati . Between 1999 and 2002 he was visiting professor at the University of Padua . Glossmann has been involved in the development of medical studies at the Medical Faculty of the private university in the Principality of Liechtenstein since 2008 . He headed the Institute for Biochemical Pharmacology at the University of Innsbruck until 2009.

Glossmann was a member of the editorial team of the Arznei-Telegram for over ten years (until 2005) and founded the first drug commission at an Austrian university clinic in Innsbruck.

As a member of the ethics committee of the Medical University of Innsbruck, he and Andreas Scheil played a key role in clearing up the urology scandal.

Scientific contribution

Receptors for inhibitors of glucose transport in the kidneys (phlorizin), for hormones (angiotensin 2, calcitonin) on plasma membranes, characterization of proteins and glycoproteins of plasma membranes

In the early 1970s, Glossmann made important contributions to the identification and characterization of proteins and glycoproteins in plasma membranes at the National Institute of Health . Together with David M. Neville Jr., who was the first to clean the (luminal) brush border membranes of the mammalian kidneys, the sodium / glucose cotransporter of these membranes (SGLT2) could be characterized biochemically with the help of tritiated phlorizin . It is noteworthy that the in vitro binding (affinity) of the (to D-glucose ) competitive blocker phlorizin was strictly dependent on the concentration of sodium ions (optimal at extracellular, lowest at intracellular concentrations) and thus offered insight into the transport mechanism. Derivatives of phlorizin are in clinical development as diabetes drugs ( canagliflozin , dapagliflozin ). Together with Kevin J. Catt, the angiotensin II receptor of the adrenal cortex was identified for the first time with radioligands and the regulation of the receptor by guanyl nucleotides (and cations) was discovered. After the glucagon receptor, this was the second peptide hormone receptor for which the coupling to G proteins in isolated membranes could be demonstrated. The calcitonin receptor was characterized in more detail in cooperation with the working group of GD Aurbach .

After his return, Glossmann devoted himself to biochemical pharmacology in Gießen, which among other things researched the elementary processes from the binding of a signal (hormone, neurotransmitter) to specific receptors, possibly via coupling proteins or messenger substances such as calcium or cyclic nucleotides to the subsequent cellular targets. He was convinced that receptors for endogenous ligands (and especially for pharmaceuticals, if no endogenous ligands exist) are ideally suited for “drug screening”, provided that appropriate “marked” samples are available for selective marking. Mocked by the classic pharmacological competition ("fidget pharmacology") at the time as "grinding and binding" , the pharmaceutical industry quickly recognized the potential of biochemical pharmacology and chose Glossmann as a scientific partner alongside others. He was provided with ligand precursors, radioactively labeled pharmaceuticals, and research and reference substances.

Tyrosine kinase, pyruvate kinase type M2, glycolysis, and malignant growth

While the interest of many pharmacologists was protein kinases, which are regulated by cyclic nucleotides, Glossmann, together with Peter Presek and Erich Eigenbrodt, described the first inhibitor of a transforming tyrosine kinase , pp 60 src, quercetin . Eigenbrodt recognized the key role of the isoenzymes of pyruvate kinase (type M2) in the control of the metabolism for the biosynthesis of nucleic acids in tumors, and together with Glossmann formulated a new interpretation of the aerobic glycolysis of many tumors discovered by Otto Warburg and the role of phosphorylation of pyruvate kinase type M2 in this happening.

Target size analysis and pharmacological receptors

In the early 1970s, there were only a few possibilities to determine the molar masses of receptor proteins for neurotransmitters and hormones and / or their associated regulatory proteins (e.g. G proteins ) in plasma membranes, unless after complete purification or photo-affinity labeling. One of the methods, known as “target size analysis” or “radiation inactivation”, uses high-energy radiation (e.g. from a linear accelerator ) to determine this. One of the few linear accelerators in Europe that could be used for such experiments existed in Giessen. Using this method, the molar masses of alpha-1 adrenoceptors and “1,4- dihydropyridine receptors ” of the voltage-dependent L-type calcium channels were determined before they were purified, photoaffinity labeled or cloned. Evidence that L-type calcium channels are oligomeric structures also came from target size analysis before the subunit composition of these membrane proteins was clarified.

L-type calcium channels

A race began to use radioactively labeled calcium antagonists to biochemically characterize the plasma membrane ion channels previously only shown using electrophysiological methods (for the first time on the heart of Harald Reuter ). This was achieved in 1981 with the 1,4-dihydropyridine nitrendipine and cardiac muscle membranes. Therefore, L-type calcium channels (more precisely: the pore-forming, transmembrane alpha-1 subunit equipped with tension sensors) are also referred to as "1,4-dihydropyridine receptors". Unexpected was the extremely high content of these receptors (CaV1.1) in skeletal muscle T-tubules, which enabled the solubilization, purification, elucidation of the subunit composition (CaV1.1: α2δ-1, β1a, γ1) and their cloning, including of of the Franz Hofmann working group . In the skeletal muscle, the subtype of the L-type calcium channels expressed there plays an elementary role in the " electromechanical coupling " (excitation-contraction coupling).

The different binding constants for 1,4-dihydropyridines, which were tissue-specific, interactions with calcium (which is bound differently by the alpha-1 subunits) and allosteric effects led to the concept of "isochannels" (at least three classes of L-type Calcium channels were postulated) and to the generally accepted model of the three receptor domains in the alpha-1 subunit. Photo-affinity ligands (azidopine, azidopamil , identical to [N-methyl-3H] (LU 49888) and azido-diltiazem) made a decisive contribution to the structure elucidation (and later identification of the amino acids involved in the receptor domains). Azidopamil, originally developed as a photoaffinity ligand for the " phenylalkylamine " receptor domain of the alpha-1 subunit of the L-type calcium channels, later proved useful in purifying the sigma-1 receptors and the emopamil binding protein.

Sigma receptors and enzymes involved in post-torture cholesterol biosynthesis

In the search for the molecular targets of the “calcium antagonist” emopamil, which has an anti-ischemic effect in animal experiments, high-affinity binding sites were discovered in the mammalian liver, which could also be photo-labeled with azidopamil. These unknown receptors have been biochemically purified, cloned and expressed. In one case it turned out to be the long-sought sigma-1 receptor; in the other case (“emopamil binding protein”) it was a so far uncharacterized enzyme of post-torture cholesterol biosynthesis. As a result, the last enzyme of cholesterol biosynthesis, delta-7-dehydrocholesterol reductase, which has not yet been characterized in mammals, was cloned and expressed. This enzyme also regulates the concentration of 7-dehydrocholesterol in the keratinocytes of the skin. 7-Dehydrocholesterol is converted into cholecalciferol (vitamin D3) via intermediate products through the action of UV-B and variants of the enzyme determine, among other factors, the vitamin D status of an individual.

Awards

  • Ludwig Schunk Prize of the Medical Faculty of the Justus Liebig University in Giessen (1979)
  • Austrian Cross of Honor for Science and Art, 1st Class (2003)
  • Letter of appreciation from the Federal Minister for Science and Research, Johannes Hahn, for the most cited Austrian scientists worldwide - together with Fred Lembeck (awarded in 2007)

Publications

Books

  • Hartmut Glossmann and Jorg Striessnig (Eds.): Methods in Pharmacology, Vol. 7: Molecular and Cellular Biology of Pharmacological Targets, Springer (2010).
  • H. Glossmann, H. Hofmann: Diseases and damage to the skin. Springer textbook 2010, pp. 423–433.

Scientific Article

  • Publications in google scholar

Web links

Individual evidence

  1. ↑ a b H. Glossmann: Institute for Biochemical Pharmacology of the Medical University (formerly the Medical Faculty of the Leopold-Franzens University) Innsbruck, in: A. Philippu: History and work of the pharmacological, clinical-pharmacological and toxicological institutes in German-speaking countries, Berenkamp , 2004, pp. 306-370; ISBN 3-85093-180-3 .
  2. ↑ Dr. med., o. Prof. Gerd W. Utermann. (No longer available online.) Archived from the original on July 14, 2014 ; Retrieved July 28, 2014 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.oeaw.ac.at
  3. ↑ Max Frimmer: Institute for Pharmacology and Toxicology Department of Veterinary Medicine at the Justus Liebig University in Gießen, in: A. Philippu: History and work of the pharmacological, clinical-pharmacological and toxicological institutes in German-speaking countries, Berenkamp, ​​2004.
  4. ↑ Kevin J. Catt: On the history of endocrinology and reproductive medicine. Springer, Berlin / Heidelberg, 1995, pp. 83-85, doi: 10.1007 / 978-3-642-79152-9_33 .
  5. ↑ Incontinence on the Inn River - Better late than never. Retrieved July 28, 2014 .
  6. ^ SJ Marx, C. Woodward, GD Aurbach, H. Glossmann, HT Keutmann: Renal receptors for calcitonin. Binding and degradation of hormones . In: The Journal of Biological Chemistry . tape 248 , no. 13 , 1973, p. 4797-4802 , PMID 4718745 (free full text).
  7. ↑ H. Glossmann, P. Presek, E. Eigenbrodt: Quercetin inhibits tyrosine phosphorylation by the cyclic nucleotide-independent, transforming protein kinase, pp60src. In: Naunyn Schmiedebergs Arch Pharmacol . 1981; 317: pp. 100-102. PMID 6269001 .
  8. ↑ E. Eigenbrodt: On the importance of the pyruvate kinase isoenzymes for the control of the carbohydrate and nucleic acid metabolism. Justus Liebig University, 1983.
  9. ^ E. Eigenbrodt, H. Glossmann (1980): Glycolysis - one of the keys to cancer . In: Trends Pharmacol Sci . 1: 240-245. doi: 10.1016 / 0165-6147 (80) 90009-7 .
  10. ↑ P. Presek, H. Glossmann, E. Eigenbrodt, W. Schoner, H. Rübsamen, RR Friis, H. Bauer: Similarities between a phosphoprotein (pp60src) -associated protein kinase of Rous sarcoma virus and a cyclic adenosine 3 ': 5'-monophosphate-independent protein kinase that phosphorylates pyruvate kinase type M2. In: Cancer Res . 1980; 40: pp. 1733-1741. PMID 6245802 .
  11. ↑ H. Glossmann: Autobiographical Sketches of a would-be Specialist in Internal Medicine, in: A. Philippu: History and Work of the Pharmacological, Clinical-Pharmacological and Toxicological Institutes in German-speaking Countries, Autobiographies, Berenkamp, ​​2014, pages 151-172, ISBN 978-3-85093-325-4 .
  12. ↑ P. Bellemann, D. Ferry, F. Lübbecke, H. Glossman: [3H] -Nitrendipine, a potent calcium antagonist, binds with high affinity to cardiac membranes . In: drug research . tape 31 , no. 12 , 1981, p. 2064-2067 , PMID 7199299 .
  13. ↑ Identification of putative calcium channels in skeletal muscle microsomes . In: FEBS Letters . tape 148 , no. 2 , 1982, p. 331-337 , PMID 6295810 (free full text).
  14. ↑ H. Glos man, J. Striessnig: calcium channels. In: Vitam Horm. 1988; 44: pp. 155-328.
  15. ↑ H. Glos man, J. Striessnig: Molecular properties of calcium channels. In: Rev Physiol Biochem Pharmacol . 1990; 114: pp. 1-105.
  16. Jump up ↑ J. Striessnig, HG Knaus, M. Grabner, K. Moosburger, W. Seitz, H. Lietz, H. Glossmann: Photoaffinity labeling of the phenylalkylamine receptor of the skeletal muscle transverse-tubule calcium channel. In: FEBS Lett. February 23, 1987; 212 (2): pp. 247-253.
  17. ↑ J. Striessnig, H. Glossmann, WA Catterall: Identification of a phenylalkylamine binding region within the alpha 1 subunit of skeletal muscle Ca2 + channels. In: Proc Natl Acad Sci U.S.A. December 1990; 87 (23): pp. 9108-9112. PMID 2174553 .
  18. ^ H. Glossmann: Origin of 7-dehydrocholesterol (provitamin D) in the skin. In: Journal of Investigative Dermatology . 2010, Volume 130 (8): pp. 2139-2141. doi: 10.1038 / jid.2010.118 .
  19. ^ V. Kuan, AR Martineau, CJ Griffiths, E. Hyppönen, R. Walton: DHCR7 mutations linked to higher vitamin D status allowed early human migration to northern latitudes. In: BMC Evol Biol. July 9, 2013; 13: p. 144. doi: 10.1186 / 1471-2148-13-144 .
  20. ^ Publications in google scholar
personal data
SURNAME Glossmann, Hartmut
BRIEF DESCRIPTION German pharmacologist
DATE OF BIRTH November 3, 1940
PLACE OF BIRTH kassel