Table Of ContentVeroffentlichungen aus der
Geomedizinischen Forschungsstelle
(Leiter: Professor Dr. Dr. h.c. mult. G. Schettler)
der Heidelberger Akademie der Wissenschaften
Supplement zu den Sitzungsberichten der
Mathematisch-naturwissenschaftlichen Klasse
Jahrgang 1993
G. Schettler H. Greten
A.I R. Habenicht (Eds.)
Cellular Metabolism
of the Arterial Wall
and Central Nervous System
Selected Aspects
With 63 Figures and 22 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
Prof. Dr. Dr. h.c. mull. Gotthard Schettler
Leiter der Geomedizinischen Forschungsstelle
Heidelberger Akademie der Wissenschaften
KarlstraBe 4, W-6900 Heidelberg, FRG
Prof. Dr. Heiner Greten
Direktor der Medizinischen Kemklinik und Poliklinik
Universitats-Krankenhaus Eppendorf
MartinistraBe 52, W-2000 Hamburg 20, FRG
Prof. Dr. Andreas 1. R. Habenicht
Medizinische Universitatsklinik, Abt. Innere Medizin I
BergheimerstraBe 58, W-6900 Heidelberg, FRG
ISBN-13: 978-3-540-56603-8 e-ISBN- 13978-3-642-84949-7
DOl: 10.1007/978-3-642-84949-7
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Contents
List of Chainnen..................................................................... IX
Opening Address
G. Schettler .............................................................................. XI
Elementary Steps in Synaptic Transmission Revealed by
Currents Through Single Ion Channels
B. Sakmann ........................................................................... I
Molecular Biology and Pathology of Alzheimer's Disease
K. Beyreuther, G. Multhaup, C.L. Masters ................................ 35
The Function of Oligodendrocytes in the Maturation
of the Brain
W. Stoffel .............................................................................. 55
Biopsy Approach to the Study and Diagnosis of Inborn
Errors of Metabolisms Affecting the Brain
D. Haust ................................................................................ 77
The Molecular Basis of Genetic Defects in HDL
Metabolism
H.B. Brewer, DJ. Rader, H.-G. Klein, K. Ikewaki,
S. Santamarina-Fojo ................................................................ 89
Lipoprotein Receptor-Mediated Oocyte Growth
W.J. Schneider, A. Vieira, I. MacLachlan, J. Nimpj .................. 105
A New Pathway of Phospholipid Biosynthesis in Animal Cells
J. A. Glomset ........................................................................ 117
How Important is Lp(a) for a Clinical Decision?
D. Seidel ............................................................................... 127
Genetic Variation of the Apolipoprotein(a) Gene and
Coronary Heart Disease
G. Utermann ..... ....... .............. ......... ........................ ...... ........ 139
The HMG-CoA Reductase Inhibitors Story
A. Endo ................................................................................ 159
LDL Receptor-Dependent Polyunsaturated Fatty Acid
Transport and Metabolism
A. l.R. Habenicht, P. Salbach, U. lanfJen-Timmen .................... 167
Receptor Mediated Hepatic Uptake of Lipoproteins
S. Jiickle, F. Rinninger, l. Greeve, U. Beisiegel,
E. Windler, H. Greten .................... .............. ...... ........ ...... ...... 179
Common Mutations Underlying the Hypertriglyceridaemia
Low HDL Syndrome
D.l. Galton .......................................................................... 193
Triglycerides, HDL, and Atherosclerosis
l.R. Patsch ..... ....... ..... .... .............. ......... ...... ... ..... ........ ......... 209
Studies on Lipoprotein Lipase
O. Stein, G. Friedman, Y. Stein 217
Smoking, Lipoproteins, and Coronary Heart Disease -
Is there a Link?
Y. Stein, O. Stein ................................................................... 223
Biochemical and Molecular Characterization of the
Scavenger Receptors
H.A. Dresel ...................................................................." ....... 233
Cellular Interactions in Atherogenesis
E. von Hodenberg, E. Pestel, M. Hautmann, l. Kreuzer,
C. Bode, W. Kubler ............................................................... 245
HMGCoA Reductase Enzyme Inhibitors, Effects on
Poliferation of Arterial Myocytes
M.R. Soma, E. Donejji, V. Dimitri, A. Corsini,
R. Paoletti .............................................................................. 255
Hemodynamic Changes after Acute Cholesterol Reduction:
Mechanisms and Mediators
P. Rubba, M. Mancini ............................................................. 265
Mechanism of Endothelial Cell Activation
P.P. Nawroth, A. Bierhaus, Y. Zhang, J. Lin, Y. Lu,
J. v. Riedesel, R. Ziegler . ................ .............................. ......... 275
Modified Lipoproteins and the Arterial Wall
M. Bihari-Varga .................................................................... 283
Hypercholesterolemia as a Cardiovascular Risk Factor
in the Elderly: Experience in Southern Italy
A. Postiglione, U. Cicerano, G. Gallotta, A. Gnasso,
M. Mancini . ................. ............................. ............. ............... 293
List of Chairmen:
Prof. Dr. J.Augustin
Merckle GmbH
Medical Research
P.O.Box 1780
7900 Ulm-Donau, Germany
Prof. Dr. GVR Born, FRCP,FRS
The William Harvey Research Institute
St.Bartholomew~ s Hospital
Medical College - Charterhouse Square
London EC1M 6BQ, Great Britain
Prof.Dr.Dr.h.c.mult.G .Schettler
Heidelberger Akademie der Wissenschaften
KarlstraBe 4
6900 Heidelberg,Germany
Prof.Dr.Y.Stein
The Hebrew University
Hadassah Medical School
Department of Experimental Medicine
and Cancer Research
P.O.Box 1172
910 10 Jerusalem, Israel
Acknowledgement
This symposium was sponsored by Merkle GmbH, Ulm/Donau, Germany
Opening Address
Gotthard Schettler
Dear friends,
dear colleagues,
On behalf of the Heidelberg Academy for the Humanities and Sciences I
welcome you to our scientific symposium.
This is one of a series of symposia in the field of molecular biology of cancer
and cardiovascular diseases, organized by the Academy in cooperation with
international societies in the last years.
Heidelberg is really a good place for such symposia, since numerous
international research institutes such as the European Molecular Biology
Laboratory, the German Cancer Research Center, the Max Planck Institute for
Medical Research, and the Center for Molecular Biology of the University
represent an attractive background, indeed. I am happy to welcome among the
participants many old friends with whom we have bad fruitful cooperations for
decades, including our Anglo-Saxon and our Italian friends.
Finally, I thank my friends and former coworkers Heiner Greten, Dietrich
Seidel, and Jan Augustin who made this meeting possible. Several social events
will give us the occasion to refresh old memories and renew old friendships.
It was nearly 50 years ago since I turned to the field of lipid research. Under
my master, Erich Letterer, I had been given the task to investigate the influence
of cholesterol on the amyloid process. I was unable to find any interrelations
after three years of investigation, but since then I have never lost my interest in
the cholesterol matter. That some of our ideas have contributed to making the
lipid hypothesis a proved fact, gives me great satisfaction at the end of my
scientific carreer. German scientists of the twenties and thirtees have made
considerable contributions in this field of research, only to mention the names
of A. Windaus, H. Wieland, E. Fischer, K. Bloch, H. Krebs, R. SchOnheimer
and also E. Klenk who, with his school, helped to elucidate the problem of lipid
storage diseases, and, last not least, S. Thannhauser, the Doyen of clinical lipid
research. I have tried with my coworkers to continue this tradition, and I am
happy about the results we obtained together with our friends of the
International Atherosclerosis Society and the European Atherosclerosis Society.
So I'm sure this symposium will bring forth new ideas for future research. In
the field of molecular biology we have advanced to areas promising important
results, also for practical medical work.
Thank you again for coming. I wish you some nice hours and days in our
beautiful Heidelberg.
Elementary Steps in Synaptic Transmission
Revealed by Currents Through Single Ion Channels*
Bert Sakmann
Max-Planck-Institut fiir Medizinische Forschung, Abteilung Zellphysiologie,
6900 Heidelberg, Germany
Correspondence to:
Prof.Dr.B.Sakmann
Max-Planck-Institut fUr
Medizinische Forschung
Abteilung Zellphysiologie
JahnstraBe 29
6900 Heidelberg, Germany
ph.: (49) 6221486 460
fax: (49) 6221486459
*With permission of the Nobel Foundation 1992
2
The plasma membrane of a cell separates its interior from the extracellular
environment and from other cells and acts both as a diffusional barrier and as
an electrical insulator. This allows differentiation of cells with specialized
functions. Coordinated behavior of multicellular organisms requires exchange
of signals between individual cells. Because the signal must be transferred from
one cell to another, it must occur by a mechanism that allows it to traverse the
insulating cell membrane. Signaling occurs in various ways via specific
receptors on the receiving cells and subsequent generation of a transmembrane
signal. The nervous system connects cells in a very specific way, and signal
transmission between individual cells takes place at contacts, called synapses,
that are anatomically and functionally highly specialized.
Synaptic signal transmission is used preferentially for rapid communication
between cells of the nervous system and those cells of peripheral organs that are
responsible for sensory transduction and for the generation of secretory and
motor activity (1, 2). Synaptic transmission includes a chemical step where the
signaling substance, called a transmitter, is released very locally from the
sending, presynaptic cell and then acts transiently on receptors of the receiving,
postsynaptic cell. The receptor is part of an ion channel and mediates, upon
occupation by the transmitter, a brief flux of ions across the postsynaptic
membrane, generating a change in the postsynaptic membrane potential.
The signal that actually initiates the cellular response of the postsynaptic cell
is the flux of ions across the postsynaptic membrane. The size, duration, and
direction of this ion flux, as well as the nature of the ions traversing the
postsynaptic membrane, determine whether this response will either activate
voltage-sensitive membrane conductances and initiate action potentials or
instead reduce the cell's electrical activity. The cellular response may also be
determined by the change in the intracellular ion concentrations, in particular,
the concentration of calcium ions, which act as a second messenger for many
cellular responses, such as contraction or secretion.
The neuromuscular junction is often thought of as a prototypical synapse. At
the neuromuscular junction, the nerve terminal of a motoneuron releases
acetylcholine (ACh) and generates end-plate potentials (EPPs), which in tum
activate voltage sensitive conductances to transmit excitation into other parts of
the muscle fiber (1). The current flow across the end-plate, induced by the
release of packets of ACh, results from the superposition of many small
individual "elementary" events (3), and there is ample evidence that
postsynaptic potentials in other synapses are also generated by the superposition
of elementary events.
This article describes the properties of elementary currents underlying
postsynaptic potentials as well as their molecular determinants. The focus is
primarily on the properties of elementary currents mediating neuromuscular
