Franz Hofmann (physician)

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Franz Bernhard Hofmann (born May 21, 1942 in Vienna ) is a German doctor and pharmacologist .

Franz Hofmann, around 2000

Life

His father was the director of the Institute for Inorganic and Analytical Chemistry at the Technical University of Vienna and later director of the Inorganic-Chemical Institute of the Ruprecht-Karls-Universität Heidelberg Ulrich Hofmann (1903–1986), his mother the doctor Renate Hofmann geb. Schubeler. Even the paternal grandfather was a chemist, while his earlier ancestors included lawyers and theologians. Franz attended the humanistic Ludwig-Georgs-Gymnasium in Darmstadt until his Abitur in 1962 . He then studied medicine in Heidelberg, at the Ludwig Maximilians University in Munich and at the Free University of Berlin . He wrote his dissertation “On the effect of some colchicine derivatives on mouse ascites tumor” with Hans Lettré (1908–1971), director of the Heidelberg Institute for Experimental Cancer Research; In 1968 he was promoted to Dr. med. PhD.

From 1970 to 1985 he worked at the Heidelberg Pharmacological Institute headed by Franz Gross (1913–1984) and then Ulrich Schwabe (* 1935). The Heidelberg period from 1973 to 1975 was interrupted by a stay at the Department of Biological Chemistry at the University of California, Davis with Edwin Gerhard Krebs , who in 1992, together with Edmond Henri Fischer, won the Nobel Prize in Physiology or for the discovery of biological control through reversible protein phosphorylation Medicine received. In 1977 Hofmann completed his habilitation with a thesis “Characterization of cAMP-dependent protein kinases” in pharmacology and toxicology. In 1985 he followed Volker Ullrich (* 1939) to the chair for physiological chemistry at the Saarland University in Homburg and in 1990 as successor to Melchior Reiter (1919–2007) to the chair for pharmacology and toxicology at the Technical University Munich , which he held until his retirement in 2008. During the Munich years, from 1992 to 1993, he was also the founding director of the Berlin Research Institute for Molecular Pharmacology , which at that time emerged from the Institute for Drug Research of the German Democratic Republic . From 1995 to 2004 he was acting head of the Institute for Physiological Chemistry at the Technical University of Munich.

He is married to the dermatologist Heidelore Hofmann geb. Schultze, with whom he has a son.

research

In the late 1950s, Earl Wilbur Sutherland and his group discovered cyclic adenosine monophosphate (cAMP) as a second messenger in the action of chemical messengers such as adrenaline . “This discovery suddenly laid down the barriers between pharmacology and biochemistry, to the great advantage of both disciplines.” Since then, the chemical or physico-chemical reaction cascades between the contact of pharmaceuticals with a cell and the response of the cell, such as a muscle contraction or relaxation, a main subject of basic pharmacological research. They are also Franz Hofmann's field of work, within which he focuses on protein kinases that are regulated by cyclic nucleotides , on voltage-dependent calcium channels and on ion channels that are regulated by cyclic nucleotides.

cGMP-dependent protein kinases

Enzyme proteins and genes

Shortly before Hofmann started at the Heidelberg Pharmacological Institute in 1970, a second cyclic nucleotide was discovered (1963), cyclic guanosine monophosphate (cGMP); (1969) the group around Günter Schultz in Heidelberg found a cGMP-forming enzyme, a guanylyl cyclase , analogous to the cAMP-forming adenylyl cyclase ; and (1968) Edwin Gerhard Krebs and his group recognized that cAMP activated a cAMP-dependent protein kinase, protein kinase A , and thus increased the phosphorylation of certain proteins. Did cGMP do the same? In the words of Hofmann and his doctoral student Guido Sold 1972: “… so far no system is known which is regulated by cGMP in mammalian tissues. In analogy to what has been found for cAMP one part of such a system could be a protein kinase regulated by cGMP. To examine such a possibility we studied the ability of cGMP and cAMP to stimulate the phosphorylation of histone by a protein kinase preparation from rat cerebellum. "The answer was: Yes, in the cerebellum of rats there was one stimulated by cGMP, by the cAMP- stimulated various protein kinases, dissolved in the cytoplasm . It was the first detection of the enzyme in mammals, having recently been found in cancers . Hofmann thus opened up a topic that has preoccupied him to this day (2011).

cGMP-dependent protein kinases have also been found in other organs, such as the heart, platelets and smooth muscle . In addition to the dissolved kinase, cGKI, there was a membrane-bound kinase, cGKII, and of the soluble kinase, noted as early as 1972, there were two isoforms formed by alternative splicing , cGKIα and cGKIβ, each consisting of two identical subunits. Finally, in 1989, Hofmann's group succeeded in cloning the cDNAs of the two cGKI isoforms at the same time as a second group and thus to determine their amino acid sequence. A little later, the cGKII was cloned in other laboratories.

Functions

The question about the functions of the cGMP-dependent protein kinases was particularly urgent because it was found in 1977 that nitrovasodilators such as nitroglycerin , long-known drugs , dilate the blood vessels by activating guanylyl cyclase and thus via cGMP. In addition, an endogenous messenger substance corresponding to nitrovasodilators was discovered in 1980, nitrogen monoxide (NO). cGMP was therefore a second messenger on a par with cAMP . Did it work in the cells - like cAMP via protein kinase A - via cGMP-dependent protein kinases? For example, did it slacken the smooth muscles of the blood vessels?

Hofmann resorted to the - molecular genetic - possibility given with knowledge of the genes, to introduce the protein kinases into cells by transfection or to remove them from cells by gene knockout . Smooth muscle cells contain both isoforms of the cGKI. The knockout experiment was clear: switching off the cGKI in mice eliminated the normal relaxation effect of nitric oxide and a cGMP-like substance on the blood vessels without affecting the relaxation effect of a cAMP-like substance. In addition, the arterial blood pressure of the cGKI-deficient mice was increased and did not respond to a nitrovasodilator.

So when the blood vessels widened, the cGMP was followed by an activation of the cGKI. The next steps are still not entirely clear. The key signal for smooth muscle cell contraction is an increase in their cytoplasmic calcium concentration . Calcium is released from the intracellular endoplasmic reticulum by the second messenger inositol trisphosphate (IP 3 ) . Hofmann's group found that cGMP inhibited the IP 3 -mediated release of calcium via activation of the cGKI. The most important aim of phosphorylation in this inhibition a novel protein has been identified, the IP and the cGKI 3 receptor of the endoplasmic reticulum and formed a complex called the authors IRAG for I P 3 r eceptor- a ssociated c G kinase MP substrate . Analogous to deletion of the cGKI, deletion of IRAG in mice also prevented or reduced the normal relaxation effect of nitric oxide and a cGMP-like substance on the blood vessels.

An important - but by no means the only - reaction cascade when nitric oxide or nitrovasodilators come into contact with blood vessels was:

"Nitric oxide → activation of a guanylyl cyclase → formation of cGMP → activation of cGKI → phosphorylation of IRAG → inhibition of the IP 3 -mediated release of calcium from the endoplasmic reticulum → vasodilation."

In summary, the following functions of the cGMP → cGKI path resulted:

  • Relaxation of the smooth blood vessel muscles through nitric oxide and related substances, as described above, but also through atrial natriuretic peptide (ANP) and related peptides, which also activate a guanylyl cyclase;
  • Relaxation of the smooth intestinal muscles and thus regulation of bowel activity; the IRAG cascade is also involved here;
  • Relaxation of the smooth muscles of the erectile tissue of the penis and thus an erection ; cGKI-deficient male mice produced much fewer offspring than normal;
  • Inhibition of platelet aggregation , another also therapeutically important effect of nitric oxide, again via IRAG;
  • Inhibition of the release of glucagon from islets of Langerhans of the pancreas ;
  • Direction of the growth cone of the axons during the growth of nerve cells ;
  • Sensitization to pain stimuli;
  • Adjustments in the nervous system such as long-term depression in the cerebellum .

Hofmann's group also switched off the cGKII through gene knockout and found the following functions of the cGMP → cGKII pathway:

  • Stimulation of the secretion of chloride ions and water into the intestinal lumen;
  • Promotion of bone formation ; the cGKII-deficient mice remained dwarfed;
  • Adjustment of the "internal clock" in the suprachiasmatic nucleus to the external time.

cAMP-dependent protein kinase

His stay at the University of California, Davis, brought Hofmann to the source of the cAMP-dependent protein kinase or protein kinase A. With Edwin Gerhard Krebs he gained new knowledge about the enzyme. Two isozymes were purified. Both consisted of an inactive complex of regulatory and catalytic subunits that disintegrated in the presence of cAMP and released the active catalytic subunits.

Back in Heidelberg, Hofmann continued to characterize the enzyme and, in collaboration with Wolfgang Trautwein from the Physiological Institute of Saarland University, directly demonstrated one of its most important functions, namely the mediation of the positive inotropic cardiac effect of adrenaline and other substances that activate β-adrenoceptors β-adrenoceptor agonists . In isolated heart muscle cells, contact with adrenaline, injection of cAMP and injection of the free catalytic subunit of protein kinase increased the influx of calcium and the force of contraction in the same way. The reaction cascade was therefore:

"Adrenaline → β-adrenoceptor → activation of adenylyl cyclase → formation of cAMP → activation of cAMP-dependent protein kinase → increase in calcium influx → increase in the force of contraction."

L-type calcium channel with (red) three groups of calcium antagonists : dihydropyridines (which nifedipine belongs to), phenylalkylamines (which verapamil belongs to) and benzothiazepines (which diltiazem belongs to)

Calcium channels

In most cellular reaction cascades, movements of calcium ions are switched on. Voltage-dependent calcium channels in the cell membrane (opened by depolarization, i.e. a reduction in the membrane potential ) are particularly important . There are several types, including the L-type channels (from l ong-lasting, with long opening periods). Hofmann, Trautwein and their colleagues in Heidelberg and Homburg had demonstrated in 1982 that their opening in heart muscle cells was promoted by activation of the cAMP-dependent protein kinase. But the details remained unknown: “The nature and localization of the proteins phosphorylated by the cAMP-dependent protein kinase have not been determined.” Similarly, three years later: “The final step of the cascade, ie phosphorylation of a Ca channel-related protein , however, remains still controversial with respect to the nature of the protein and its relation to the Ca channel. "

In Heidelberg Hofmann worked with the physiologist Johann Caspar Rüegg (* 1930), who was interested in calcium in smooth muscles. In Homburg, Wolfgang Trautwein was a physiological partner. In addition, the pharmacologist Hartmut Glossmann (* 1940) in Gießen was scientifically close to him. Glossmann researched calcium antagonists such as verapamil , nifedipine and diltiazem , which blocked the L-calcium channels and were therefore used, for example, in coronary artery disease . In 1981 he first used radioactively labeled calcium antagonists to investigate L-type calcium channels.

Channel proteins and genes

This environment promoted what began in Homburg in 1985, namely the cleaning of the binding sites for radioactively labeled calcium antagonists in the tissue, their identification with the largest of four proteins of the L-type calcium channels and the recombination of the purified proteins in artificial lipid bilayers to form functioning channels. Protein chemistry was again followed by molecular genetics. After Japanese and US laboratories had cloned the largest subunit, α 1 , and a second, α 2 δ, in 1987 and 1988 , Hofmann's group cloned the cDNA of the β subunit in 1989 and the cDNA of the γ subunit in 1990: with α 1 / α 2 δ / β / γ the channel was complete.

For the cDNA cloning, all research groups had used their particularly high content of L-type calcium channels because of the skeletal muscles of rabbits. Other tissues followed. They contained related, but not necessarily identical, subunits, and all in all, we now know 11 α 1 genes (and thus α 1 proteins), 4 α 2 δ genes (and thus α 2 δ proteins) for the large family of voltage-dependent calcium channels ), 4 β genes (and thus β proteins) and 4 γ genes (and thus γ proteins), a molecular diversity that reflects the diversity of the physiological and pharmacological properties of the channels. The α 1 subunit forms the pore and contains the voltage-sensitive amino acids and - in the case of L-type channels - the binding sites for calcium antagonists. The first cloned channels in the skeletal musculature are called Ca v 1.1 in today's nomenclature , the most important channels in the heart and smooth muscles Ca v 1.2., Some channels in sensory cells Ca v 1.3.

Functions

Basically, the physiological significance of the channels has long been known: If the extracellular space does not contain calcium, the heart stops beating. Molecular genetic work has brought many details to light.

  • The Ca v 1.2 canal is essential for the heart and smooth muscles. Mice with complete gene knockout still died in utero due to a lack of cardiac activity. Even after selective (“conditional”) knockout in the smooth muscles, the animals were seriously ill and soon died of intestinal obstruction caused by paralysis of the intestinal muscles. Also, the blood pressure was too low and did not respond to vasoconstrictors such as norepinephrine.
  • The Ca v 1.2 channel also contributes to the release of insulin from the β cells of the pancreas and

However, one problem that was at the very beginning has not yet been solved: the problem of the reaction cascade between the β-adrenoceptors of the heart muscle and the increase in the influx of calcium through the L-type channels and thus the force of contraction, formulated in 1982 and then again in 1985. In 2008, the Munich group confirmed that the cAMP-dependent protein kinase phosphorylated the α 1 subunit of the Ca v 1.2 channel in cardiac muscle cells of mice on a specific serine , serine 1298. Prevention of phosphorylation by replacing the serine with the non-phosphorylatable amino acid alanine did not reduce the increase in calcium influx and contraction force due to the β-adrenoceptor agonist isoprenaline . The β-adrenoceptor cascade undoubtedly included phosphorylation by the cAMP-dependent kinase, but: “What is the physiological substrate of the cAMP kinase in the Ca v 1.2 channel complex?” The question persists.

Synthesis and receptors of cGMP. NO activates soluble ones (GCs), ANP activates a membrane-bound guanylyl cyclase (GCp). cGMP acts on phosphodiesterases (PDE), on a cGMP kinase and on CNG channels. "Using these CNG channels, you can see this figure."

Channels controlled by cyclic nucleotides

The cAMP- and cGMP-dependent protein kinases are not the only molecules that continue cAMP and cGMP signaling cascades. There are two groups of cation channels, the opening of which is promoted by direct binding of cAMP or cGMP, without would take place phosphorylation: the CNG channels, of c yclic n ucleotide- g ated, and the HCN channels , of h yperpolarization-activated , c yclic n ucleotide-gated. The binding site is an intracellular amino acid sequence near the C-terminus of the channel subunits CNBD, c yclic n ucleotide- b inding d omain.

CNG channels

It has been known since 1985 that cGMP mediates the perception of light in the rods and cones of the retina of the eye, and since 1987 it has been known that cAMP mediates the perception of fragrances in the olfactory cells of the nose . The cyclic nucleotides bind directly to CNG channels in the sensory cells and open them; Unlike the voltage-dependent calcium channels, for example, the channels are hardly sensitive to changes in the membrane potential.

The first subunit of a CNG channel, CNGA1, was cloned from the retina of cattle by a Japanese-German research group in 1989; the second, CNGA2, was cloned from the olfactory mucosa of rats by a US research group in 1990 . CNGA1 is a subunit in the retinal rods, not the retinal cones (responsible for color vision). Hofmann's group made the first contribution in 1994. Based on the known nucleotide sequences of the CNGA1 and CNGA2 genes, i.e. a priori molecular genetic, they cloned the cDNA of a subunit, CNGA3, in a completely different tissue, namely the kidney of cattle. In addition to the kidney, the subunit was found in the heart and testes, and soon it was identified with a subunit found in 1993 in the cones of the retina of chickens. A total of six CNG subunits are known today, which combine to form tetramers for channel formation . The function of the channels in non-sensory cells is unclear. Perhaps by opening cGMP it triggers an influx of calcium ions.

Elimination of the CNGA3 gene in mice hardly interfered with their growth, behavior or reproduction, but had one serious consequence: the cones on their retinas were diminished shortly after birth and disappeared completely by the age of eight months; every cone function was absent. In human terms: the animals were color-blind . In fact, some people's color blindness is due to a mutation in the CNGA3 gene.

In a textbook scheme of the intracellular sites of action of cGMP, Hofmann commented on the CNG channels: "You can see this figure using these CNG channels."

HCN channels

CAMP also promotes the opening of a group of cation channels which their investigators found so strange that they named the electrical currents through the channels I f ( f unny) or I q ( q ueer). A third designation I h derives from just this peculiarity: namely, that the channels (of the membrane potential reduction) can not be opened like most voltage-gated ion channels by depolarization but by H yperpolarisation (increasing the membrane potential); the channel opening then causes depolarization by the influx of sodium ions. Since the late 1970s, one suspects one or the cause of the rhythmic firing of action potentials in nerve cells and, particularly fascinatingly, in the sinus node cells of the heart, which initiate the heartbeat, in the currents .

Hofmann's Munich group assumed that cAMP could bind to a similar CNBD in the I f / q / h channels as in the CNG channels. Indeed, starting with a computer-aided search in nucleotide sequence databases, the group discovered four new genes and the corresponding proteins for the I f / q / h channels in the brains of mice and human hearts in 1998 and 1999 . At the same time, a US group and a second German group were discovered. The two characteristics aperture through hyperpolarization and opening promotion by cyclic nucleotides led to the designation HCN channels, HCN1 to HCN4, h yperpolarization-activated, c yclic n ucleotide-gated. In the cell membranes, like in the CNG channels, the subunits for the formation of pores form tetramers, mostly consisting of different subunits.

HCN channels are mainly found in nerve cells and in the heart. HCN2 in particular is widespread in the brain. In the sinus node of the heart of humans and mice, HCN4 and HCN2 form the tetramers (80% HCN4 and 20% HCN2). Also, the downstream conduction system of the heart has HCN channels.

In the brain, HCN channels contribute to adaptations such as long-term potentiation, learning, and memory. Mice with a deletion of the HCN2 gene lacked the I h current in the (thalamo-cortical) neurons running from the thalamus to the cerebral cortex . So there was no depolarizing current, and this increased the resting membrane potential . Decreased motor activity and the electroencephalogram showed absence epilepsy . Human absence epilepsy also results from a hyperpolarization of thalamo-cortical neurons - HCN2 is of importance for the disease.

Pacemaker action potential with underlying ion currents

Finally, when it comes to the HCN channels in the heart, they are a mystery to research. The fascinating assumption was that they were mainly responsible for the rhythmic action potentials in the sinus node, the pacemaker action potentials , and thanks to the promotion of their opening by cAMP for the positive chronotropic effect of β-adrenoceptor activation - just like the cAMP protein kinase for its positively inotropic Effect is primarily responsible. In the HCN2 knockout mice, however, the mean heart rate and the acceleration due to cAMP and isoprenaline were unchanged; the heartbeat was just less regular.

Mice with a deletion of the HCN4 gene, the gene for the predominant HCN subunit of sinus node cells, died in utero on about the 10th day of embryo. Hearts drawn before death were slow to beat and normal, mature pacemaker action potentials were absent. Apparently the heartbeat, which was too slow due to a lack of mature pacemaker activity, was not enough to supply the embryo with blood after the 10th day. A big surprise came, however, "a big surprise", when HCN4 was switched off by a conditional knockout only after birth in 8-week-old mice. The I h current was then greatly reduced, the sinus node cells were slightly hyperpolarized due to the reduction in a depolarizing current, and the heart sometimes stopped (for a few tenths of a second). Otherwise, however, the mice lived apparently unimpaired, their mean heart rate was unchanged, isoprenaline increased it normally (to a maximum of 700 per minute), and in the presence of isoprenaline the sinus node cells developed mature pacemaker action potentials.

What replaced the missing HCN4 subunit in the formation of normal pacemaker action potentials? What, if not HCN4 or HCN2, converted β-adrenoceptor activation and cAMP into cardiac acceleration? The riddle becomes a paradox if one adds that in people with a mutation in the HCN4 gene the heart rate was very much reduced and did not react to cAMP. Where does the species difference come from? Like the question about the steps from cAMP to increase the contraction force of the heart (see above), the question about the steps from cAMP to increase the heart rate continues.

In the meantime, the HCN channels of the heart have achieved therapeutic importance. In 1979 a derivative of clonidine , St 567 or Alinidin, was described that selectively slowed the heart. It works, as we know today, by blocking the HCN channels in the sinus node. Another "sinus node inhibitor", ivabradine , has been used for coronary artery disease since 2006.

Teaching

Since 2001 Hofmann has been writing the chapter “Effects of pharmaceuticals on the organism: general pharmacodynamics” of the textbook “General and Special Pharmacology and Toxicology” published in 2001 by Wolfgang Forth, Dietrich Henschler , Walter Rummel , Ulrich Förstermann and Klaus Starke . He has been co-editor since 2005, most recently the 10th edition.

Since 2003 he has been writing the chapters “Smooth muscle tone regulation” and “Voltage-dependent Ca 2+ channels” of the “Encyclopedic Reference of Molecular Pharmacology”.

student

The following scientists have completed their habilitation with Franz Hofmann (with year of habilitation):

  • Veit Flockerzi (1987), later professor for experimental and clinical pharmacology and toxicology in Homburg (Saar)
  • Peter Ruth (1994), later professor for pharmacology and toxicology in Tübingen
  • Martin Biel (1995), later professor for pharmacology for natural sciences at the Ludwig Maximilians University in Munich
  • Wolfgang Dostmann (1996), later Professor of Pharmacology at the University of Vermont in Burlington (Vermont)
  • Alexander Pfeifer (1997), later professor for pharmacology and toxicology in Bonn
  • Norbert Klugbauer (1998), later professor of pharmacology in Freiburg im Breisgau
  • Thomas Kleppisch (1999)
  • Xiangang Zong (1999)
  • Andreas Ludwig (2000), later professor for pharmacology and toxicology in Erlangen
  • Gerhard Rammes (2001)
  • Jens Schlossmann (2001), later professor for pharmacology and toxicology in Regensburg
  • Robert Feil (2003), later professor at the Interdisciplinary Institute for Biochemistry in Tübingen
  • Andrea Welling (2003)
  • Jörg Wegener (2004)
  • Horst Thiermann (2005)
  • Juliane Stieber (2006)
  • Sven Moosmang (2006)

recognition

In 1998 the Tongji Medical University in Wuhan , and in 2004 the Chinese Academy of Sciences appointed Hofmann professor honoris causa . He has been a member of the Bavarian Academy of Sciences since 2001, a member of the German Academy of Sciences Leopoldina since 2001 and a member of the Academia Europaea since 2003 . In 2002 he gave the Ludwig Aschoff lecture of the Freiburg Medical Society in Freiburg im Breisgau . He also received the Max Planck Research Prize in 2002, the Feldberg Foundation Prize in 2003, the 1st Class Cross of Merit of the Federal Republic of Germany in 2004 and the Bavarian Order of Merit in 2006 .

Individual evidence

  1. ^ Hanns-Peter Boehm: Ulrich Hofmann 1903–1986 . In: Chemical Reports . 120, 1987, pp. XXXVII-L. doi : 10.1002 / cber.19871201224 .
  2. ^ Hofmann on the website of the Technical University of Munich. Retrieved January 17, 2013.
  3. ^ HP Rang and MM Dale: Pharmacology , 2nd edition. Edinburgh, Churchill Livingstone 1991, p. 38. ISBN 0-443-04110-5
  4. ↑ E. Böhme, K. Munske and G. Schultz: Formation of cyclic guanosine-3 ', 5'-monophosphate in various tissues of the rat. In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology . 264, 1969, pp. 220-221
  5. ↑ Franz Hofmann and Guido Sold: A protein kinase activity from rat cerebellum stimulated by guanosine-3 ': 5'-monophosphate . In: Biochemical and Biophysical Research Communications . 49, 1972, pp. 1100-1107. doi : 10.1016 / 0006-291X (72) 90326-9 .
  6. ↑ a b Veronika Leiss, Andreas Friebe, Andrea Welling, Franz Hofmann and Robert Lukowski: Cyclic GMP kinase I modulates glucagon release from pancreatic α-cells . In: Diabetes . 60, 2011, pp. 148-156. doi : 10.2337 / db10-0595 .
  7. ↑ W. Wernet, V. Flockerzi and F. Hofmann: The cDNA of the two isoforms of bovine cGMP-dependent protein kinase . In: FEBS Letters . 251, 1989, pp. 191-196. doi : 10.1016 / 0014-5793 (89) 81453-X .
  8. ↑ Alexander Pfeifer, Peter Klatt, Steffen Massberg, Lars Ny, Matthias Sausbier, Christoph Hirneiß, Ge-Xing Wang, Michael Korth, Attila Aszódi, Karl-Erik Andersson, Fritz Krombach, Artur Mayerhofer, Peter Ruth, Reinhard Fässler and Franz Hofmann: Defective smooth muscle regulation in cGMP kinase I-deficient mice . In: EMBO Journal . 17, 1998, pp. 3045-3051. doi : 10.1093 / emboj / 11.17.3045 .
  9. ↑ Jens Schlossmann, Aldo Ammendola, Keith Ashman, Xiangang Zong, Andrea Huber, Gitte Neubauer, Ge-Xing Wang, Hans-Dieter Allescher, Michael Korth, Matthias Wilm, Franz Hofmann and Peter Ruth: Regulation of intracellular calcium by a signaling complex of IRAG, IP 3 receptor and cGMP kinase Iβ . In: Nature . 404, 2000, pp. 197-201. doi : 10.1038 / 35004606 .
  10. ↑ Matthias Desch, Katja Sigl, Bernhard Hieke, Katharina Salb, Frieder Kees, Dominik Bernhard, Angela Jochim, Beate Spiessberger, Klaus Höcherl, Robert Feil, Susanne Feil, Robert Lukowski, Jörg W. Wegener, Franz Hofmann and Jens Schlossmann: IRAG determines nitric oxide- and atrial natriuretic peptide-mediated smooth muscle relaxation . In: Cardiovascular Research . 86, 2010, pp. 496-505. doi : 10.1093 / cvr / cvq008 .
  11. ↑ a b F. Hofmann, R. Feil, T. Kleppisch and J. Schlossmann: Function of cGMP-dependent protein kinases as revealed by gene deletion . In: Physiological Reviews . 86, 2006, pp. 1-23. doi : 10.1152 / physrev.00015.2005 .
  12. ↑ Petter Hedlund, Attila Aszódi, Alexander Pfeifer, Per Alm, Franz Hofmann, Marianne Ahmad, Reinhard Fässler and Karl-Erik Andersson: Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice . In: Proceedings of the National Academy of Sciences . 97, 2000, pp. 2349-2354. doi : 10.1073 / pnas.030419997 .
  13. ↑ Melanie Antl, Marie-Luise von Brühl, Christina Eiglsperger, Matthias Werner, Ildiko Konrad, Thomas Kocher, Matthias Wilm, Franz Hofmann, Steffen Massberg and Jens Schlossmann: IRAG mediates NO / cGMP-dependent inhibition of platelet aggregation and thrombus formation . In: Blood . 109, 2007, pp. 552-559. doi : 10.1182 / blood-2005-10-026294 .
  14. ↑ Alexander Pfeifer, Attila Aszódi, Ursula Seidler, Peter Ruth, Franz Hofmann and Reinhard Fässler: Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II . In: Science . 274, 1996, pp. 2082-2086. doi : 10.1126 / science.274.5295.2082 .
  15. ^ Franz Hofmann, Joseph A. Beavo, Peter J. Bechtel and Edwin G. Krebs: Comparison of adenosine 3 ': 5'-monophosphate-dependent protein kinase from rabbit skeletal muscle and bovine heart muscle . In: The Journal of Biological Chemistry . 250, 1975, pp. 7795-7801. PMID 170270 .
  16. ↑ a b c W. Osterrieder, G. Brum, J. Hescheler, W. Trautwein, V. Flockerzi and F. Hofmann: Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca 2+ current . In: Nature . 298, 1982, pp. 576-578. doi : 10.1038 / 298576a0 .
  17. ↑ U. Förstermann: Pharmacology of the cardiovascular system. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke: General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pages 449-485. ISBN 978-3-437-42522-6
  18. ↑ a b M. Kameyama, F. Hofmann and W. Trautwein: On the mechanism of β-adrenergic regulation of the Ca channel in the guinea-pig heart . In: Pflügers Archive - European Journal of Physiology . 405, 1985, pp. 285-293. doi : 10.1007 / BF00582573 .
  19. ↑ Peter Ruth, Veit Flockerzi, Egbert von Nettelbladt, Jochem Oeken and Franz Hofmann: Characterization of the binding sites for nimodipine and (-) - desmethylmethoxyverapamil in bovine cardiac sarcolemma . In: European Journal of Biochemistry . 150, 1985, pp. 313-322. doi : 10.1111 / j.1432-1033.1985.tb09023.x .
  20. ↑ Franz Hofmann, Wolfgang Nastainczyk, Axel Röhrkasten, Toni Schneider and Manfred Sieber: regulation of the L-type calcium channel . In: Trends in Pharmacological Sciences . 8, 1987, pp. 393-398. doi : 10.1016 / 0165-6147 (87) 90103-9 .
  21. ↑ Peter Ruth, Axel Röhrkasten, Martin Biel, Eva Bosse, Stefan Regulla, Helmut E. Meyer, Veit Flockerzi and Franz Hofmann: Primary structure of the β subunit of the DHP-sensitive calcium channel from skeletal muscle . In: Science . 245, 1989, pp. 1115-1118. doi : 10.1126 / science.2549640 .
  22. ^ E. Bosse, S. Regulla, M. Biel, P. Ruth, HE Meyer, V. Flockerzi and Franz Hofmann: The cDNA and deduced amino acid sequence of the γ subunit of the L-type calcium channel from rabbit skeletal muscle . In: FEBS Letters . 267, 1990, pp. 153-156. doi : 10.1016 / 0014-5793 (90) 80312-7 .
  23. ^ F. Hofmann, M. Biel and V. Flockerzi: Molecular basis for Ca 2+ channel diversity . In: Annual Review of Neuroscience . 17, 1994, pp. 399-418. doi : 10.1146 / annurev.ne.17.030194.002151 .
  24. ^ William A. Catterall, Edward Perez-Reyes, Terrance P. Snutch and Joerg Striessnig: International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels . In: Pharmacological Reviews . 57, 2005, pp. 411-425. doi : 10.1124 / pr.57.4.5 .
  25. ↑ Josef Platzer, Jutta Engel, Anneliese Schrott-Fischer, Kurt Stephan, Sergio Bova, Howard Chen, Hui Zheng and Joerg Striessnig: Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca 2+ channels . In: Cell . 102, 2000, pp. 89-97. doi : 10.1016 / S0092-8674 (00) 00013-1 .
  26. ↑ Sven Moosmang, Verena Schulla, Andrea Welling, Robert Feil, Susanne Feil, Jörg W. Wegener, Franz Hofmann and Norbert Klugbauer: Dominant role of smooth muscle L-type calcium channel Ca v 1.2 for blood pressure regulation . In: EMBO Journal . 22, 2003, pp. 6027-6034. doi : 10.1093 / emboj / cdg583 .
  27. ↑ Nicole Langwieser, Carl J. Christel, Thomas Kleppisch, Franz Hofmann, Carsten T. Wotjak and Sven Moosmang: Homeostatic switch in Hebbian plasticity and fear learning after sustained loss of Ca v 1.2 calcium channels . In: The Journal of Neuroscience . 23, 2010, pp. 8367-8375. doi : 10.1523 / JNEUROSCI.4164-08.2010 .
  28. ↑ Toni Lemke, Andrea Welling, Carl Johannes Christel, Anne Blaich, Dominik Bernhard, Peter Lenhardt, Franz Hofmann and Sven Moosmang: Unchanged β-adrenergic stimulation of cardiac L-type calcium channels in Ca v 1.2 phosphorylation site S1928A mutant mice . In: The Journal of Biological Chemistry . 283, 2008, pp. 34738-34744. doi : 10.1074 / jbc.M804981200 .
  29. ^ A b Franz Hofmann: Effects of pharmaceuticals on the organism: general pharmacodynamics. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke: General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pages 5-24. ISBN 978-3-437-42522-6
  30. ^ Franz Hofmann, Martin Biel and U. Benjamin Kaupp : International Union of Pharmacology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels . In: Pharmacological Reviews . 57, 2005, pp. 455-462. doi : 10.1124 / pr.57.4.8 .
  31. ↑ a b c Kimberley B. Craven and William N. Zagotta: CNG and HCN channels: two peas, one pod . In: Annual Review of Physiology . 68, 2006, pp. 375-401. doi : 10.1146 / annurev.physiol.68.040104.134728 .
  32. ↑ Martin Biel, Xiangang Zong, Madeleine Distler, Eva Bosse, Norbert Klugbauer, Manabu Murakami, Veit Flockerzi and Franz Hofmann: Another member of the cyclic nucleotide-gated channel family, expressed in testis, kidney, and heart . In: Proceedings of the National Academy of Sciences . 91, 1994, pp. 3505-3509. doi : 10.1073 / pnas.91.9.3505 .
  33. ↑ Martin Biel, Mathias Seeliger, Alexander Pfeifer, Konrad Kohler, Andrea Gerstner, Andreas Ludwig, Gesine Jaissle, Sascha Fauser, Erberhart Zrenner and Franz Hofmann: Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3 . In: Proceedings of the National Academy of Sciences . 96, 1999, pp. 7553-7557. doi : 10.1073 / pnas.96.13.7553 .
  34. ↑ Andreas Ludwig, Xiangang Zong, Michael Jeglitsch, Franz Hofmann and Martin Biel: A family of hyperpolarization-activated cation channels . In: Nature . 393, 1998, pp. 587-591. doi : 10.1038 / 31255 .
  35. ↑ Andreas Ludwig, Xiangang Zong, Juliane Stieber, Roger Hullin, Franz Hofmann and Martin Biel: Two pacemaker channels from human heart with profoundly different activation kinetics . In: EMBO Journal . 18, 1999, pp. 2323-2329. doi : 10.1093 / emboj / 18.9.2323 .
  36. ↑ a b c d e Martin Biel, Christian Wahl-Schott, Stylianos Michalakis and Xiangang Zong: Hyperpolarization-activated cation channels: from genes to function . In: Physiological Reviews . 89, 2009, pp. 847-885. doi : 10.1152 / physrev.00029.2008 .
  37. ↑ a b Andreas Ludwig, Thomas Budde, Juliane Stieber, Sven Moosmang, Christian Wahl, Knut Holthoff, Anke Langebartels, Carsten Wotjak, Thomas Munsch, Xiangang Zong, Susanne Feil, Robert Feil, Marike Lancel, Kenneth R. Chien, Arthur Konnerth, Hans-Christian Pape, Martin Biel and Franz Hofmann: Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2 . In: EMBO Journal . 22, 2003, pp. 216-224. doi : 10.1093 / emboj / cdg032 .
  38. ↑ TJ Feuerstein: Anticonvulsants, convulsives - pharmacotherapy of epilepsies. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke: General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pp. 283-293. ISBN 978-3-437-42522-6
  39. ↑ Juliane Stieber, Stefan Herrmann, Susanne Feil, Jana Löster, Robert Feil, Martin Biel, Franz Hofmann and Andreas Ludwig: The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in embryonic heart . In: Proceedings of the National Academy of Sciences . 100, 2003, pp. 15235-15240. doi : 10.1073 / pnas.2434235100 .
  40. ↑ Stefan Herrmann, Juliane Stieber, Georg Stöckl, Franz Hofmann and Andreas Ludwig: HCN4 provides a "depolarization reserve" and is not required for heart rate acceleration in mice . In: EMBO Journal . 26, 2007, pp. 4423-4432. doi : 10.1038 / sj.emboj.7601868 .
  41. ^ W. Kobinger, C. Lillie and L. Pichler: N-allyl-derivative of clonidine, a substance with specific bradycardic action at a cardiac site. In: Naunyn-Schmiedeberg's Archives of Pharmacology . 306, 1979, pp. 255-262, doi: 10.1007 / BF00507111 .
  42. ↑ K. Aktories, U. Förstermann, F. Hofmann and K. Starke: General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009. ISBN 978-3-437-42522-6
  43. ↑ Stefan Offermanns and Walter Rosenthal (eds.): Encyclopedic Reference of Molecular Pharmacology. Berlin, Springer-Verlag 2003. ISBN 3-540-42843-7
  44. ↑ Member entry by Prof. Dr. Franz Hofmann (with picture and CV) at the German Academy of Sciences Leopoldina , accessed on July 15, 2016.
personal data
SURNAME Hofmann, Franz
ALTERNATIVE NAMES Hofmann, Franz Bernhard (full name)
BRIEF DESCRIPTION German physician and pharmacologist
DATE OF BIRTH May 21, 1942
PLACE OF BIRTH Vienna