Angelo Azzi Zdenek Drahota Sergio Papa (Eds.)

Molecular Basis of Membrane-Associated Diseases

With 121 Figures

Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong

Prof. Dr. A N G E L O A Z Z I Institut für Biochemie und Molekularbiologie Universität Bern Bühlstraße 28 CH-3012 Bern

Prof. Z D E N E K D R A H O T A Institute of Physiology Czechoslovak Academy of Sciences Videnska 1083 CS-142 20 Praha 4

Prof. S E R G I O PAPA Institute of Medical Biochemistry and Chemistry University of Bari Piazza G . Cesare 1-70124 Bari

ISBN 3-540-50744-2 Springer-Verlag Berlin Heidelberg New York ISBN 0-387-50744-2 Springer-Verlag New York Berlin Heidelberg

Library of Congress Cataloging-in-Publication Data. Molecular basis of membrane-associated diseases. Based on a symposium held in Prague on 14-16 July 1988. Includes index. 1. Cell membranes-Abnormalities-Congresses. 2. Mitochondrial membrancs-Abnormalitics-Congresses. 3. Lysosomal storage diseases-Congres­ses. I. Azzi. A . (Angelo) I I . Drahota, Ζ. I I I . Papa. S. [ D N L M : 1. Cell Membranc-pathology-congresses. 2. Diseases-ctiology-congresses. 3. Membranes-pathology-congresscs. QS 532.5.M3 M718 1988] RB152.M64 1989 616.07 89-11270

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Contents

1 Plasma Membrane and Control of Cell Growth and Differentiation

Insulin Receptor Kinase and Insulin Action Ε . V A N O B B E R G H E N , R. B A L L O T T I , Y . L E M A R C H A N D - B R U S T E L and J . C . S C I M E C A (With 3 Figures) 3

Structural and Functional Aspects of Signal Transduction by Receptor Tyrosine Kinases. Y . Y A R D E N 14

Nerve Growth Factor (NGF): Physiological Functions and Regulation of Its Synthesis. D . L I N D H O L M , R. H E U M A N N , G . D . B O R A S I O and H. T H O E N E N 2 2

Signal Transduction by Growth Factor Receptors W. H . M O O L E N A A R (With 3 Figures) 2 9

Altered Regulation of Receptor-Associated Tyrosine Kinases in Human Tumors. R M . C O M O G L I O , M.F. D I R E N Z O , G . G A U D I N O , S. G I O R D A N O , L . N A L D I N I and C. P O N Z E T T O 35

The Role of Plasma Membrane Phospholipids in Cellular Pathology A. S T R U N E C K A , J . P A L E C E K , L . K R P E J S O V A , N.I . E L D E S O U K I , P. F O L K and J . M A C H A (With 7 Figures) 53

Changes in the Structure and Function of the Red Cell Membrane Skeleton and Hemolytic Anemias. P. J A R O L I M , S.-C. L I U , T H . L . C O E T Z E R , M. L A H A V and J . P A L E K (With 1 Figure) 64

Regulation of Intracellular C a 2 + in Pancreatic Acinar Cells by Membrane Pumps and Channels. R . L . D O R M E R (With 3 Figures) . . . . 71

Control of Protein Kinase C Function by Activators and Inhibitors C H . W. M A H O N E Y and A . Azz i (With 2 Figures) 84

2 Regulation of Membrane Channels

K + Channels: Structure, Function, Regulation, Molecular Pharmacology and Role in Diseased States. H . B E R N A R D I , J.-N. B I D A R D , M. F O S S E T , M. H U G U E S , C H . M O U R R E , H . R E H M , G . R O M E Y , H . SCHMID-A N T O M A R C H I , H . S C H W E I T Z , J . R. D E W E I L L E and M. L A Z D U N S K I (With 9 Figures) 99

V I I I Contents

Voltage-Dependent Calcium Channels: Structure and Regulation in Normal and Abnormal States. M.M. H O S E Y , F. C. C H A N G , C M . O ' C A L L A H A N , J . PTASIENSKI, J . B A R H A N I N and M. L A Z D U N S K I (With 6 Figures) 112

Cell Membrane Abnormalities in Genetic Hypertension G . B I A N C H I , P. F E R R A R I , S. S A L A R D I , P. SALVATI, M. F E R R A N D I , L . T O R I E L L I and B . R . B A R B E R 124

Transmembrane Cation Transport: An Approach to the Study of the Molecular Basis of Hypertension. L . M A Z Z A N T I , R. A. R A B I N I , N. C E S T E R , C. ROMANINI and E . B E R T O L I 130

Transmembrane Ionic Fluxes in the Brain in Energy-Depleted Cells Β. K . S IESJÖ (With 9 Figures) 134

3 Mitochondrial Genetic Diseases

Mitochondrial Diseases. S. D I M A U R O , A. L O M B E S , H . N A K A S E , M. Z E V I A N I , R. R I Z Z U T O , C . T M O R A E S and E . A. SCHON 157

Mitochondrial Myopathy: Biochemical Approaches to Respiratory Chain-Linked Electron Transfer and Energy Coupling C P L E E , M . E . M A R T E N S , P L . P E T E R S O N , S . H . TSANG and M. SCIAMANNA (With 6 Figures) 167

Phosphorus Magnetic Resonance Spectroscopy ( 3 1 P NMR) as a Tool for in Vivo Monitoring of Mitochondrial Muscle Disorders Z . A R G O V (With 5 Figures) 183

Cytochemical and Immunocytochemical Studies of Human Mitochondrial Myopathies. M. A . JOHNSON (With 7 Figures) 200

Regulatory Complexity of Cytochrome c Oxidase and Its Defective Manifestation in Mitochondrial Diseases. B. K A D E N B A C H , F . - J . H Ü T H E R , U . B Ü G E , A . S C H L E R F and M. A. JOHNSON (With 7 Figures) 216

Fibroblasts and Cytochrome c Oxidase Deficiency D . M . G L E R U M , B . H . ROBINSON and R. C A P A L D I (With 2 Figures) . . . 228

Human Cytochrome c Oxidase Deficiencies; Structural and Functional Aspects. K . M . C SINJORGO, A . O . M U I J S E R S , H . R . S C H Ö L T E , Α . Β . P. V A N K U I L E N B U R G , J . J . V A N B E E U M E N , E . M . B R O U W E R - K E L D E R ,

J . A . B E R D E N , P.A. B O L H U I S and J . M . T A G E R (With 3 Figures) 239

4 Mitochondrial Metabolic Diseases

Brown Adipose Tissue, Diet-Induced Thermogenesis and Genetic Obesity. T. S O U K U P , H . R A U C H O V Ä , J . D O S O U D I L O V A and Z . D R A H O T A (With 5 Figures) 257

Contents I X

Acute and Long-Term Regulation of Brown Adipose Tissue Thermogenesis: Physiological and Pathological Implications J . H O U S T E K , J . K O P E C K Y , D. JANI'KOVÄ, J . B E D N A R , Μ. H O L U B , T. S O U K U P , M. M I K O V A and K . V I ' Z E K (With 7 Figures) 265

Molecular Composition, Fluidity of Membranes and Functional Properties of Human Liver Mitochondria and Microsomes G H . B E N G A (With 3 Figures) 285

Changes in Erythrocyte and Platelet Membrane Fluidity in Childhood Obesity. G . F E R R E T T I , A. T A N G O R R A , P L . G I O R G I , M. D O T T I , G . C U R A T O L A and E . B E R T O L I 303

Skeletal Muscle Mitochondria and Phospholipase Activity in Malignant Hyperthermia. K . S . C H E A H 309

The Antimitochondrial Antibodies (ΑΜΑ) of Primary Biliary Cirrhosis (PBC) . H . B A U M and M. FUSCONI 323

Toxicity, Antioxidants, and Metabolism. L . P A C K E R (With 3 Figures) . . 335

5 Cancer and Energy Metabolism

Mitochondrial H + - A T P Synthase Under Normal and Pathological Conditions. S. PAPA, F. G U E R R I E R I , F. Z A N O T T I and F. C A P U A N O (With 8 Figures) 347

Antitumor Effect of Drugs Interfering with Mitochondrial Biogenesis S. K U Z E L A , K . L U C I A K O V A , J . K O L A R O V and B . D . N E L S O N (With 6 Figures) 359

6 Lysosomes and Peroxisomes in Health and Disease

The Complex of /3-Galactosidase, Neuraminidase and "Protective Protein" in Lysosomes: Molecular Characterization of the "Protective Protein". A . D ' A Z Z O , N. G I L L E M A N S and N. G A L J A R T (With 5 Figures) . 371

The Role of Activator Proteins in Glycolipid Degradation and Storage Diseases. E . C O N Z E L M A N N (With 3 Figures) 379

Solute Translocation Across the Lysosome Membrane: Physiology, Pathology and Pharmacology. J . B . L L O Y D , T. K O O I S T R A , S. F O R S T E R , S . J . B I R D and G.P. I V E S O N (With 6 Figures) 395

The Peroxisomal /^-Oxidation Systems: Characteristics and (Dys) Functions in Man. R . J . A . W A N D E R S , C.W.T. VAN R O E R M U N D , Μ. J . A . VAN W I J L A N D , R . B . H . S C H U T G E N S , H . VAN DEN B O S C H and J . M . T A G E R 407

χ Contents

Genetic Heterogeneity in Inherited Disorders with a Generalized Impairment of Peroxisomal Functions: Visualization by Immunofluorescence Microscopy of Peroxisome Assembly After Somatic Cell Fusion of Complementary Cell Lines S. B R U L , E . A . C . W I E M E R , M. O O S T H U I Z E N , A. W E S T E R V E L D , R . VAN D R I E L , A . S T R I J L A N D , R . B . H . S C H U T G E N S , Η . VAN D E N B O S C H , R . J . A . W A N D E R S , A . W. S C H R A M and J . M. T A G E R (With 2 Figures) . . 420

Subject Index 429

List of Contributors You will find the addresses at the beginning of the respective contribution

Argov, Ζ 183 Azzi, A. 84

Ballotti, R. 3 Barber, B . R . 124 Barhanin, J . 112 Baum, Η. 323 Bednar, J . 265 Benga, Gh. 285 Berden, J . A . 239 Bernardi, H . 99 Bertoli, E . 130, 303 Bianchi, G . 124 Bidard, J.-N. 99 Bird, S .J . 395 Bolhuis, P.A. 239 Borasio, G . D . 22 Brouwer-Kelder, Ε. M. 239 Brul, S. 420 Büge, U . 216

Capaldi, R. 228 Capuano, F . 347 Cester, N. 130 Chang, F . C . 112 Cheah, K . S . 309 Coetzer, Th. L . 64 Comoglio, P . M . 35 Conzelmann, E . 379 Curatola, G . 303

d'Azzo, A . 371 de Weille, J . R . 99 DiMauro, S. 157 DiRenzo, M . F . 35 Dormer, R . L . 71 Dosoudilovä, J . 257 Dotti, M. 303 Drahota, Z . 257

ElDesouki, N .I . 53

Ferrandi, M. 124 Ferrari, P. 124 Ferretti, G . 303 Folk, P. 53 Forster, S. 395 Fosset, M. 99 Fusconi, M. 323

Galjart, N. 371 Gaudino, G . 35 Gillemans, N. 371 Giordano, S. 35 Giorgi, P . L . 303 Glerum, D . M . 228 Guerrieri, F . 347

Heumann, R. 22 Holub, M. 265 Hosey, M . M . 112 Houstek, J . 265 Hugues, M. 99 Hüther, F . - J . 216

Iveson, G . P . 395

Janikovä, D. 265 Jarolim, P. 64 Johnson, M. A. 200,216

Kadenbach, Β. 216 Kolarov, J . 359 Kooistra, T. 395 Kopecky, J . 265 Krpejsovä, L . 53 Kuzela, S. 359

X I I List of Contributors

Lahav, M. 64 Lazdunski, M. 99, 112 Lee, C P . 167 Le Marchand-Brustel, Y . 3 Lindholm, D. 22 Liu , S.-C. 64 Lloyd, J . B. 395 Lombes, A . 157 Luciakovä, K. 359

Mächa, J . 53 Mahoney, Ch. W. 84 Martens, M . E . 167 Mazzanti, L . 130 Mikovä, M. 265 Moolenaar, W . H . 29 Moraes, C T . 157 Mourre, Ch. 99 Muijsers, A . O . 239

Nakase, H . 157 Naldini, L . 35 Nelson, B . D . 359

O'Callahan, C M . 112 Oosthuizen, M. 420

Packer, L . 335 Palecek, J . 53 Palek, J . 64 Papa, S. 347 Peterson, P. L . 167 Ponzetto, C 35 Ptasienski, J . 112

Rabini, R . A . 130 Rauchovä, H . 257 Rehm, H . 99 Rizzuto, R. 157 Robinson, Β. Η. 228 Romanini, C . 130 Romey, G . 99

Salardi, S. 124 Salvati, P. 124 Schlerf, A. 216 Schmid-Antomarchi, H . 99 Schölte, H . R . 239 Schon, E . A . 157 Schräm, A . W . 420 Schutgens, R . Β . Η. 407, 420 Schweitz, Η. 99 Sciamanna, Μ. 167 Scimeca, J . C 3 Sies jö ,B .K. 134 Sinjorgo, K . M . C 239 Soukup, T. 257, 265 Strijland, A . 420 Struneckä, A . 53

Tager, J . M . 239,407,420 Tangorra, A . 303 Thoenen,H. 22 Torielli, L . 124 Tsang, S . H . 167

van Beeumen, J . J . 239 van den Bosch, H . 407, 420 van Driel, R. 420 van Kuilenburg, A . B. P. 239 Van Obberghen, E . 3 van Roermund, C W. T. 407 van Wijland, M . J . A . 407 Vizek, K. 265

Wanders, R . J . A . 407, 420 Westerveld, A. 420 Wiemer, E . A . C . 420

Yarden, Y . 14

Zanotti, F . 347 Zeviani, M. 157

Nerve Growth Factor (NGF): Physiological Functions and Regulation of Its Synthesis D . L I N D H O L M 1 , R . H E U M A N N , G . D . B O R A S I O and H . T H O E N E N

1 Introduction

The physiological role of N G F as a neurotrophic factor in the peripheral nervous system is well established. N G F is essential for the development and maintenance of specific functions of peripheral sympathetic and neural-crest derived sensory neurons. N G F acts as a retrograde messenger between the target organs and the innervating neurons. The regionally different quantities of N G F in target tissues reflect the density of innervation by NGF-responsive neurons, which transport N G F in membrane-confined compartments to the perikaryon after N G F is bound via specific membrane receptors. Although the physiological function of N G F is well documented and a large number of NGF-specific effects on target neurons have been identified, there are two main questions which remain to be elucidated, namely the nature of the second messenger(s) evolving from the binding of N G F to its receptor and the mode of regulation of N G F synthesis in the target tissues. A better understanding of this regulation would provide the prerequisite for a rational approach to the pharmacological modification of N G F synthesis. This is of particular interest because it has recently become apparent that N G F is essential for the preservation of the function of the cholinergic neurons of the basal forebrain nuclei. These neurons are consistently affected in Alzheimers's disease and their impaired function seems to be largely responsible for the cognitive deficits of this disease.

2 Physiological Functions of NGF

Earlier work on N G F was mainly focussed on the role of N G F in embryonic development and differentiation of the peripheral nervous system (Levi-Mon-talcini 1987). N G F has been shown to regulate the survival of peripheral sym­pathetic and neural-crest derived sensory neurons during restricted periods of development (cf. Levi-Montalcini and Angeletti 1968; Greene and Shooter 1980; Thoenen and Barde 1980). This has been conclusively demonstrated in exper­iments on neonatal rodents where administration of anti-NGF antibodies leads to

Department of Neurochemistry, Max-Planck-Institute for Psychiatry, A m Klopferspitz 18 A,D-8033 Martinsried/Munich, F R G 'To whom correspondence should be addressed

A. Azzi, Z. Drahota and S. Papa Molecular Basis of Membrane-Associated Diseases © Springer-Verlag Berlin Heidelberg 1989

Nerve Growth Factor 23

enhanced cell death in the NGF-responsive neuronal population, whereas ex­ogenous N G F can rescue neurons which normally would die during the period of natural cell death. In addition, N G F is also required for differentiation and maintenance of function of the peripheral sympathetic and sensory neurons in adult life. Thus, N G F has been shown to regulate synthesis of specific enzymes which are involved in neurotransmitter production, such as tyrosine hydroxylase and dopamine /^-hydroxylase as well as a series of neuron-specific peptides (cf. Otten 1984; Johnson E.M. et al. 1986; Thoenenetal. 1987). In the peripheral target fields N G F is synthesized in very low amounts and is retrogradely transported to the cell bodies of NGF-responsive neurons after being taken up via specific cell surface receptors (cf. Schwab et al. 1982). It has also been shown that the density of innervation of target organs by NGF-responsive neurons correlates with the levels of N G F and its mRNA (Korsching and Thoenen 1983; Heumannetal. 1984; Shelton and Reichardt 1984). Moreover, interruption of the retrograde axonal transport of N G F following axotomy or by pharmacological interference (e.g. colchicine treatment which results in disassembly of microtubuli) leads to degenerative changes in the NGF-responsive neurons, demonstrating that N G F acts as a retrograde messenger between the periphery and the innervating neurons (cf.Thoenen etal. 1987).

In contrast to sympathetic neurons in the peripheral nervous system, central adrenergic neurons neither respond to N G F nor carry N G F receptors (Konkol et al. 1978; Schwab et al. 1979). However, evidence for a trophic role of N G F in the central nervous system became apparent when it was shown that the cholinergic neurons of the basal forebrain nuclei express N G F receptors and exhibit specific retrograde transport of N G F (Schwab et al. 1979; Seiler and Schwab 1984). The cholinergic neurons have also been shown to respond to N G F with an increase in the levels of choline acetyltransferase (ChAT), the enzyme responsible for synthesis of the cholinergic neurotransmitter acetylcholine. This has been shown both in neonatal rats (Gnahn et al. 1983), in aggregate cultures of fetal forebrain (Honegger and Lenoir 1982), and in adult rats after partial fimbria lesions, i.e. of the septo-hippocampal connection (Hefti et al. 1984). The cell bodies of the cholinergic neurons are situated in the medial septal nuclei, in the diagonal band of Broca and in the basal nuclei of Meynert. Their fiber tracts project to the hippocampus, neocortex and olfactory bulb (cf. Cuello and Sofroniew 1984) and these innervated areas exhibit relatively high levels of N G F and NGF-mRNA as compared to other brain regions (Korsching et al. 1985; Whittemore et al. 1986; Shelton and Reichardt 1986). In analogy to the situation in the peripheral nervous system, there is a close correlation between the levels of N G F and its mRNA and the density of cholinergic innervation. Even within the rat hippocampus there are differences between N G F levels of various regions, e.g. the CA3, CA4 and dentate gyrus region have higher levels of N G F protein compared with the CA1-CA2 region and this is reflected in the density of cholinergic innervation (cf. Korsching 1986; Thoenen et al. 1987). Recent autoradiographic receptor binding studies on sections from adult rat brain have clearly demonstrated the presence of N G F receptors on these cholinergic neurons (Riopelle et al. 1987; Raivich and Kreutzberg 1987). Moreover, N G F levels and ChAT activity in rat hippocampus

24 D. Lindholm et al.

increase in parallel during postnatal development, further supporting a role of N G F in this septo-hippocampal system (Auburger et al. 1987). Likewise, fimbria lesion experiments have shown that exogenous N G F administrated through an infusion pump can rescue cholinergic neurons of the basal forebrain nuclei which would otherwise degenerate following the transection (Hefti 1986; Kromer 1987; Williamset al. 1986).

3 Mechanism(s) of Action of NGF

Although many actions of N G F on target neurons have been described, the overall mechanism by which N G F exerts its effects is still unknown. This also holds true for the most important long-term effect of N G F , namely its survival-promoting activity on NGF-responsive neurons. N G F receptors on sensory (Sutter et al. 1979) and sympathetic neurons (Godfrey and Shooter 1986) and on PC 12 pheo-chromocytoma cells (Hosang and Shooter 1985) have been identified and antibodies to the N G F receptor have been produced (Chandler et al. 1984; Ross et al. 1984). Moreover, binding studies have shown the existence of both high- and low-affinity N G F receptors on target cells which are encoded by the same mRNA. However, the mechanism for conversion between the two forms is not known but the high-affinity receptor seems to be responsible for most of the biological action of N G F , at least in PC12 cells (Green et al. 1986). Recently, both human and rat N G F receptors have been cloned (Johnson D. et al. 1986; Radeke et al. 1987) and the molecular data demonstrate that the N G F receptor belongs to a novel class of membrane receptors which lack an intrinsic tyrosine kinase activity. N G F is also known not to affect neuronal proliferation which is in contrast to most growth factors which have a mitogenic activity on their target cells (cf. Thoenen et al. 1987).

Previous studies have shown that intracellular microinjection of N G F into the cytoplasm of PC 12 cells, bypassing the receptor, fails to elicit differentiation which is readily seen with N G F in the culture medium (Heumann et al. 1981). Conversely, microinjected, function-blocking, anti-NGF antibodies do not inhibit N G F action on PC 12 cells. These studies led to the conclusion that N G F acts by a distinct second messenger system, the nature of which remains to be elucidated (Heumann et al. 1981). The results of recent studies have suggested a role for the ras oncogene product in N G F signal transduction. Introduction of purified, activated, ras protein into PC 12 cells can elicit differentiation (Bar-Sagi and Feramisco 1985), and microinjected, anti-ras antibodies are able to block the effect of N G F on these cells (Hagag et al. 1986). The exact site of action of ras or of ras-like proteins in the signal transduction cascade induced by N G F is not known. Further downstream, transcriptional activators are most probably involved in regulating NGF-specific gene expression. Interestingly, N G F (Greenberg et al. 1985) as well as ras protein (Stacey et al. 1987) are known to transiently increase expression of the c-fos proto-oncogene product which is thought to be involved in transcriptional regulation. Milbrandt (1987) has recently described another putative transcrip­tional activator gene whose transcription is strongly induced in PC 12 cells by short-term N G F treatment.

Nerve Growth Factor 25

4 Regulation of NGF Synthesis and Implications for Treatment of Alzheimer's Disease

In Alzheimer's disease the cholinergic neurons of the basal forebrain nuclei are consistently affected and there is an atrophy and /or loss of these neurons during the course of this disease (Coyle et al. 1983; Pearson et al. 1983). Moreover, the impaired synthesis of acetylcholine is one of the earliest detectable signs of Alzheimer's disease and correlates well with the cognitive deficits observed (Francis et al. 1985). In view of the fact that these cholinergic neurons are also the target of N G F in the central nervous system, the hypothesis was put forward that N G F could play a role in this disease (Hefti and Weiner 1986). The idea that Alzheimer's disease results from an insufficient supply of N G F for these neurons has recently been disputed by Goedert and co-workers (1986). These authors demonstrated that the levels of NGF-mRN A in the cerebral cortex of patients with Alzheimer's disease are not different from the corresponding levels found in age-matched controls. Nevertheless, the following observations support the notion that pharmacological amounts of N G F are of potential value in treatment of Alzheimer's disease by supporting the cholinergic neurons undergoing atrophy or degeneration. Thus, it has been demonstrated that chronic administration of N G F over a period of 4 weeks can improve memory function, as shown by behavioural tests, and can counteract cholinergic cell body atrophy observed in a subpopulation of aged rats (Fischer et al. 1987). Moreover, studies on septo-hippocampal lesions clearly show that exogenous N G F has a beneficial effect in preventing cholinergic cell degeneration in the septal area after a transection of the fimbria (Hefti 1986; Kromer 1987; Williams et al. 1986). Likewise, N G F injections (Will and Hefti 1985) or transplantation of fetal cholinergic neurons into the hippocampus (Dunnett et al. 1982; Gage and Björklund 1986) can improve both learning and memory deficits observed in rats after such a lesion.

In view of these findings it seems justified to consider N G F supplementation as a possible therapeutic approach for the treatment of patients suffering from Alzheimer's disease. This could be achieved by either local administration of recombinant human N G F , of peptides with NGF-like functions or by enhancing endogenous N G F synthesis by pharmacological agents. However, a prerequisite for such an intervention is a better understanding of the physiological mechanisms by which N G F is regulated in vivo. Recent studies in the peripheral nervous system have shown that specific polypeptide factors are involved in the control of N G F synthesis in the nonneuronal cells. Using the rat sciatic nerve as a model system under conditions of degeneration and regeneration after a nerve lesion, we were able to show that macrophages play an important role in N G F regulation (Heumann et al. 1987; Thoenen et al. 1988). Interleukin-1, a lymphokine produced by these cells, was found to be the responsible agent increasing NGF-mRN A levels in the nonneuronal cells (Lindholm et al. 1987). Recent studies indicate that the action of IL-1 involves activation of phospholipase A2 and that IL-1 has a dual effect on NGF-mRN A. Thus, IL-1 enhances N G F gene transcription and also increases the stability of NGF-mRNA in cultured sciatic nerve fibroblasts (Lindholm et al. 1988).

26 D. Lindholm et al.

The studies on the regulation of N G F synthesis in the central nervous system are less advanced compared with the peripheral nervous system. We have recently obtained evidence that IL-1 and other mesenchymal growth factors can influence NGF-mRNA levels in cultured rat astrocytes. We are currently studying the complex interplay of various growth factors in controlling NGF-mRNA synthesis in the central nervous system both in vivo and in vitro. Moreover, since it has very recently been reported that hippocampal neurons can also express NGF-mRNA (Rennert and Heinrich 1986; Ayer-LeLievre et al. 1988) this adds a new dimension to studies concerned with the regulation of N G F synthesis in the central nervous system.

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Nerve Growth Factor 27

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28 D. Lindholm et al.: Nerve Growth Factor

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Subject Index

Abelson murine leukemia virus ( A M u L V ) 38 Acetylcholine 71,73 Acute lymphoblastic leukemia ( A L L ) 39, 41 Acyl-CoA oxidase deficiency 411 Adducin 126 Adiposity 257 Adrenoleukodystrophy ( N A L D ) 420 Alkoxyl radicals 336 Aminoacridines 90 3,4-aminopyridines 104 Amylase 73 Ankyrin-band 3 interaction 65 Anoxia

changes in extracellular ion concentrations 137

suddenly occurring 137 terminal depolarization 137

Antibodies antimitochondrial ( Α Μ Α ) 323-334

reactivity with bacteria 328 phosphotyrosine 37

Antioxidants 335-343 Anti tumor drugs 359-367 Apamin receptor 102

expression during brain ontogenesis 102 sensitive channels 102

Arachidonic acid 286, 289 Arylsulfatase 379 ATPase (Ca~ +) activation by calmodulin 76 ATPase

( C a 2 + , M g 2 + ) activated 71 activated by C a 2 + 75

ATPsynthase 347-358 and neoplasia 350 during liver regeneration 351

Au-S-malate 90 Auranofin 90

inhibition of neutrophil N A D P H oxidase 90 Autocriny 35,41,44 Autoerythrocyte sensitization syndrome 53 Autosensitization

against patient red blood cells 53 antibodies against mitochondria ( Α Μ Α ) 323 circulating antibodies against Ca channels 120 pathogenesis 53 PS as a provocative factor 53

α-tocopherol see Vitamin Ε

α-tocopherylquinone 91 ft-1 peptide 113

sequence homology to voltage-dependent Na channels 114

substrate for protein kinase C 118

Bcr-abl 38 tyrosine kinase 40

Biliary diseases 299 Bombesin 29,31,42-45

growth factor 41 in growth control 42 in small-cell lung carcinomas mitogenic 42 trigger for tyrosine kinase 42

Bradykinin 30,32 Brown adipose tissue 257-264, 265-284

acute regulation 270 biogenesis 275 deiodinase activity 270 hyperfunction 277 in diabetic obese (db/db) mice 276 in genetic obesity 276 in heat production 266 in myopathic hamsters 269 in nude mouse 278 in pathological states 276 in the febrile response 277 ligands of uncoupling protein 271 malfunction 277 mitochondria 259 morphological data perinatal development 266, 272 regulation 266,270 thermogenetic function 257

ß-carotene 338 ß-cell 104 ß-D-galactosidase 371 ß-hexosaminidase A 380

C-ablgene 39 C-abl protein 39

structural alteration 40 C-erb-B2 46,47 C-fms 47 C-fos 24 C-kit 47

430 Subject Index

C-met 47 C-onc proteins 47 C-trk 46.47 C a 2 +

activated photoproteins 72 activation of K + channel 75, 99 free cytoplasmic concentration 77 GTP induced C a 2 + release 78 indicators 72 influx inhibited by antimycin A 74 inhibition of cell entry 74 ionophores 72 iontophoresis 72 mechanism of cell entry 74 movements in pancreatic acinar cells 73 release

induced by C a 2 + 78 induced by Ins(l,4,5)P 3 78 occurs in discrete organelles 78 stimulated by GTP 78

store 77 C a 2 + channels

antagonists competitive (AP7) 143 non-competitive (MK801) 143 of the dihydropyridine type 143

antibodies and autoimmune disease 120 effectors 113 in excitable and nonexcitable cells 112 L-type

in disease 119 increased in cardiomyopathic hamsters 119 regulation by phosphorylation 117

voltage-dependent 112, 141 purification and characterization 113

Calcineurin 117 Calciosomes 78 Calsequestrin 78 Carcinoma cells 30 Cerebral metabolic rate 134 Cerebro-hepato-renal (Zellweger)

syndrome 420 Cholecystokinin 71 Chronic myelogenous leukemia ( C M L ) 38 Chronic progressive external ophthalmoplegia

(CPEO) ^224 Cinnarizine 74 CI7HCO- 3 antiporter 145 CP-channels

control by membrane potential 72 in the apical membrane 72

Class 1 oncogenes 36, 37 intracellular targets 37

Class 2 oncogenes 37 C M L 39 Cold adaptation 265 Complementation analysis 420 Complex I V 216

CPEO 200,206 Creatine kinase (CK) 186 CSF-1 15 CSF-l-R 14 Cystinosis 403 Cytochrome c 298 Cytochrome c oxidase 218,228,240,260.297,360

deficiencies 216-226, 228-236, 239-250 clinical heterogeneity 244 encephalomyopathies 245 in CPEO 245 in human 239 infantile myopathies 244 lack of specific subunit 248 ophthalmoplegia 245 type-A 246 type-B 247

differences in the small subunits 243 different gene families 221 from rat brown fat tissue 220 immunocytochemical studies 207 immunopurified from muscle biopsies 246 isoenzymes 243 microphotometric assay 207 nuclear and mitochondrial genome

products 228 subunits 240

from adult and fetal tissues 219 specific antisera 224 tissue-specific isoenzymes 241

D-2-amino-phosphonoheptanoate D-2-amino-phosphonovalerate (AP5) D A G (see also diacylglycerol) 85

activation of protein kinase C 87 Dantrolene 317 DCCD-binding protein 347 Deiodinase 268

catecholamine-induced activation 269 type I and I I 268

Dendrotoxins 108 Diacylglycerol ( D A G ) 30, 58, 61, 73 1,4-dihydropyridine (DHP) 113 DPH-as fluorescent probe 306 Duchenne dystrophy 194

EGF (epidermal growth factor) 16. 29. 38. 44-46

chemical crosslinking 16 intermolecular activation 16 microaggregation 16 monomenc and dimeric forms 16 signal transduction 17

Electron transfer 177 Elliptocytosis (herediatary) 66 Encephalomyelopathy 161 Energy metabolism 135

progressive reduction 136

Subject Index 431

Epidermal growth factor (see EGF) 29 Epilepsy with ragged red fibers (see also

M E R R F ) 159 Erb-B 14

oncogene 29 Exocytosis 72

Fabry disease 388 Fatal infantile mitochondrial myopathy 161,

229 Fluorescence polarization 307 F-met-leu-phe 89 Free oxygen radicals 300

Galactosialidosis 372,373 Galanin 105 Ganglioside GM3 390 Gastric carcinoma 44 Gaucher disease 387 Genetically dysgenic mouse mdg/mdg 119

lack of receptor for C a 2 + channel effectors 119

Glibenclamide 104 Glutathione 340 Glutathione peroxidase 341 Glycolipid catabolism 382 Glycosphingolipids 379 Gold-type antirheumatic drugs 90 G M 2 activator 380, 382 G-proteins 32 Growth factors 14

bombesin 41 E G F 16

chemical crosslinking 16 intermolecular activation 16 microaggregation 16 monomeric and dimeric forms 16 signal transduction 17

hemopoietic growth factor CSF-1 35 N G F 22-28

and cholinergic neurons 23 antibodies 24 as a neurotrophic factor 22 in Alzheimer's disease 25 insufficient supply 25 intracellular microinjection 24 levels of choline acetyltransferase

(ChAT) 23 macrophages role in regulation 25 mechanism(s) of action 24 nature of the second messenger(s) 22 pharmacological modification 22 physiological function 22 preventing cholinergic cell

degeneration 25 regional distribution 22 regulation of synthesis 23 required for differentiation 23

response 23 retrograde axonal transport 23 trophic role 23

P D G F 14,29,37,38,44,46

H-9 88 Heinz bodies 67 Hemichromes 67 Hemolytic anemia

effect of hemoglobin denaturation 67 microangiopathy 66 spectrin mutants 66 transfusion-dependent 66

Hemopoietic malignancies 38 Hereditary spherocytosis 57 Histamine 30,32

human HeLa cells growth 31 Human fibroblasts 44 Hydrogen peroxide 336 Hydroxyl radicals 337 Hypermetabolism of non-thyroid origin 167 Hyperphagia 258 Hypertension 124-128, 129-132

defects in N a + transport 130 essential

animal model 124 N a + , K + ATPase activity 131 pregnancy-induced (PIH) 130

Hypoglycemia 146 coma 134 ionic gates involved 140 preischemic 139

Inflammation and cancer 337 Inositol phospholipids 29, 30 1,4,5-inositol triphosphate (seealso IP :,) 58 Insulin 3-13,44,45

antibodies 3 binding and kinase activation 4 dose-response 4 metabolic and growth-promoting effects 10 phosphorylating cellular substrates 5 receptor 17

antiphosphotyrosine antibodies 6 autophosphorylation 6 chimeric constructions 17 domains 17 heterodimers 17 kinase hyperactivity 6 kinase impairment 6 ligand-induced kinase activation 17 mutation 7 phosphorylation 3 phosphorylation reversibility 6 seryl (and threonly) phosphorylation 8 specificity of effects 6 structure 3 tyrosine kinase 4

432 Subject Index

release 104 tolbutamide and sulfonylurea 104

sensitive protein kinase 3 transmembrane signalling 3

Interleukin-1 25 Ionophore ( A 23187) 58

and phophatidylinositol 4-phosphate 59 I P 3 (Inositol-l,4,5-trisphosphate) 30, 61, 75

77, 85 IP 4 (Inositol-l,3,4,5-tetraphosphate) 75

K + channels 57, 99-110, 105 ATP-regulated 104

opened by galanin 105 presence ain cardiac cells 105 presence in neurons 105 sulfonylureas block 104

Ca 2 +-ativated 99 T E A (tetraethylammonium) block 99 voltage-dependent 107

Kearns-Sayre syndrome (KSS) 159, 200, 206 223

age of onset of clincal symptoms 201 with lacticacidemia (Robinson) 229

Ketamine 149 Kidney cross-transplantation 125 KSS see Kearns-Sayre syndrome

Lambert-Eaton myasthenic syndrome 120 Leigh's disease (subacute necrotizing

encephalomyelopathy) 157, 161,200 Liver regeneration 350 Long-term potentiation 108 Loose coupling 157 Luft disease 158 Lung cancer

incidence 338 Lysosomes 381,395-406

carriers for neutral amino acids 399 entry of dipeptides 399 hydrolases 381 inborn errors 402 membrane permeability 395 metabolite-porters 399 passive diffusion 398 storage disease 381

Lysosphingolipids 90

Magnetic resonance spectroscopy (see also N M R and 3 , P - N M R ) 183

Malignant hyperthermia ( M H ) 309-322 Malignant hyperthermia

ATPase activity 313 C a 2 + accumulation 310 C a 2 + release 316 C a 2 + transport 310 halothane 310 in healthy pigs 309

phospholipase A 309 phospholipase A 2 activity 314 uncoupling of oxidative phosphorylation

310 Malignant transformation 14 Μ antigens 324 M 2 antigen 328

identity with 70 k D antigen 329 non-mitochondrial location 329

Mast cell degranulating peptide 107 McArdle's syndrome 192 Μ E L AS (mitonchondrial encephalomyophaty

with lactic acidosis) 159, 223 in complex I deficiency 159

Membrane fluidity 285-302, 303-308 M E R F F syndrome 161, 202, 223

transmission by maternal inheritance 159 Merocyanine-540 54

binding in homologous RBC 54 Metachromatic leukodystrophy ( M L D ) 388 Microcytoma 41 Milan hypertensive rat strain (MHS) 124 Mitochondria

abnormal 189 assays of preparations 170 content of respiratory chain carriers 170 diseases 157 enzyme defects

benign infantile myopathy 161 complex I 160 complex I I 160 complex I V 161 CPT deficiency 159 cytochrome c oxidase (COX) 161 cytochrome c oxidase deficiency 167 different genetic errors 161 fatal infantile myopathy 161 Krebs cycle 160 Leigh syndrome 161 M E R R F syndrome 161 oxidation-phosphorylation coupling 160 respiratory chain 160 spontaneous mutation of m t D N A 161 substrate utilization 159

fragment preparation 168 in cancer chemotherapy 365 lipid composition 286 membranes amino acid composition 290

fluidity probed by spin labeling 291 protein-lipid interactions 291

morphological abnormalities 201 myopathies 167-180, 183-189, 200-214, 223

abnormal morphological features 228 cytochrome measurement 234 defect

characterization 232 cytochrome c oxidase 231

fibroblasts as diagnostic tools 230

Subject Index 433

immunodetection 232 lactate to pyruvate ratio (L/P) 231 lactic acidosis 229 maternal inheritance 239 maternal transmission 212 northern analysis 235 subunit specific antisera 230 with encephalopathy 159

partial reactions of the respiratory chain 170 preparations 168

from Kearn-Sayre syndrome tissues 171 semimicro-techniques 178

respiratory functions 310 tightly coupled, from skeletal muscle 171 transformation into thermogenic 275

Mitochondrial encephalomyopathy with lactic acidosis (see also M E L A S ) 159

Morris hepatoma 3924A 351 Muscular dystrophy 194 Myopathies

megaconial 157 mitochondria 187.200

carnitine palmitoyltransferase (CPT) deficiency 157

enzyme defects complex I 200 complex I I I 200 complex I V 200

major gene deletions 158 microphotometric assays 200 morphological classification criteria 157 NADH-coenzyme Q reductase 188 M P nuclear magnetic resonance ( N M R )

spectroscopy 158 ragged red fibers. RRF 157 reduction in post-excrcise recovery of

PCr 187 steroid experimental therapy 195 vitamins K : > (menadione) therapy 194

pleoconial 157 Myotonic muscle dystrophy 102

N-acetyl-a-neuraminidase (sialidase) 371 N a + channel 99

sensitivity to apamin 99 N a + retention in MHS 125 Na + /Ca 2 + exchange 71,76 N a + / H + antiporter 145 N a + / H + exchange

activation of 32 amiloride-sensitive 32 deactivation 33 differentiation process 33

NADH-dehydrogenase (complex I) 25 Neoplastic cell markers 37 Neu , 15 Neuroblastoma 89 Neurohormone 42

N G F (nerve growth factor) 25 and cholinergic neurons 23 antibodies 24 in Alzheimer's disease 25 insufficient supply 25 intracellular microinjection 24 level of choline acetyltransferase (ChAT) 23 macrophages role in regulation 25 mechanism(s) of action 24 nature of the second messenger(s) 22 pharmacological modification 22 physiological function 22 preventing cholinergic cell degeneration 25 regional distribution 22 response 23

Nifedipine 74 N M R 183

ATP concentration 184 determination of intracellular pH 183 isolated heart mitochondria in vitro 185 phosphocreatine (PCr) and inorganic

phosphates (Pj) detection 183 spectroscopy 158

Obesity 257 genetic forms

db/db mouse 258 ob/ob mouse 258

synthesis and turnover of cholesterol 303 Omega-phosphonic acid 143 Oncogenes (see also specific oncogenes)

class -2 35 coded tyrosine kinases 36 control of cell proliferation 36 tyrosine phosphorylation 36

Organic hydroperoxides 336 Oxidative phosphorylation 134, 216, 359

in rapidly growing tumors respiratory chain-linked 176 uncoupling 266

Oxytetracycline 362

P|45 44 biological functions 45 dephosphorylation 46 in liver cells 46 tyrosine phosphorylation 45

Pancreatic acinar cell 71 PCr/Pj 190

age-related reduction 194 at rest 193 carnitine deficiency 190 in acute disorders 195 in chronic polymyositis 194 in resting muscle PCr/Pj 195 malignant hyperthermia 190 non specificity for primary mitochondrial

diseases 196

434 Subject Index

recovery after exercise 193 in myophosphorylase deficiency 192

PDGF 37,38,44,46 Peroxisomes 407

/3-oxidation 407-419 energetic aspects 410 inborn errors 411 induction 410

in detoxification reactions, serving 415 inherited disorders 420-428 in mammalian metabolism 407 physiological importance 407 thiolase deficiency 411 visualization by indirect immuno­

fluorescence 423 Phenylalkylamines (PAA) 113 Philadelphia chromosome 38 Phorbol esters 33,73 Phosphatidylethanolamine (PE) 53 Phosphatidylinositol 4,5-biphosphate

(PIP 2) 58 Phosphatidylserine (PS) 53 Phosphatidylserine reaction with TNBS 54 Phosphoinositide signalling system 58 Phospholipase C 29, 73 Phospholipids

asymmetry 53,54 plasma membrane 53 reaction of RBC with TNBS 55

Phosphorylation potential (PP) 186 Phosphotyrosine antibodies 37 Plasma

abnormalities in hypertension 124-128 lipids 304 thermolabile factor 56

3 1 P-NMR 183-198 indicators of mitochondrial disease 189 monitoring of therapy 194 spectrum of muscle at rest 183

Primary biliary cirrhosis (PBC) 323-334 antimitochondrial antibodies ( Α Μ Α ) 323 cross-reacting epitopes 332 oxygen-free radicals (oxidants) 335 pathogenesis 332

Progressive external ophthalmoplegia (see also CPEO) 200

Protective protein 371-378 c D N A 373

Protein kinase C 30, 38, 58, 73, 84-94,127 α,β and γ forms 85 activation of 31, 84, 85

by aplysiatoxin 87 by D A G by lead 87 by phorbol diesters 87 by teleocidin 87 by tumor promoters 87

by unsaturated fatty acids 86 and E G F receptor phosphorylation 86 apparent molecular weight 84 auto-phosphorylation of α and γ forms 86 differential distribution in brain 85 in human neutrophils 85 in normal and ras-transformed 3T3

fibroblasts 85 inhibitors 88,90

affecting C a 2 + binding 88 affecting the site of interaction with the

protein substrate 88 platelet aggregation 89 redistribution 85 regulatory domain 86

preparation by tryptic digestion 86 v

substances affecting 89 respiratory burst of neutrophils 89

Protein transport 364 Proton conductivity 353 Pseudogenes 223 Pyropoikilocytosis 66

Quin 2 72

Ragged-red fibers 201,223 Ras 24 Ras-like proteins 24 RBC (red blood cells)

cytoskeleton 55 visualization in human cells 55

merocyanine 540 binding 55 phospholipids reaction with TNBS 55 presence of tubulin and actin 55 tubulin in human cells 55

Receptors aggregation 18 and channel regulation 112 autoregulation 37 bombesin complex in small-cell lung

carcinomas 43 cellular activation 18 collision-coupling 18 dimerization 18 EGF 16 for apamin 102 G-protein coupled 15 gl uta mate 142

activation kainate (K) 142 N-methyl-D-aspartate (N or

N M D A ) 142 quisqualate (Q) 142

growth factors 29-34 lacking tyrosine kinase activity 24 monoclonal and polyclonal antibodies 18 PDGF 45 photoaffinity labelling 113

Subject Index 435

signal transduction by EGF 16 tyrosine kinase 14-21, 32, 35-52 tyrosine kinases (RTK's) 14

Red blood cell (see also RBC) 53 membrane skeleton 64 stability and oxidant damage 67

Renal transplant rejection 67 Respiratory burst of neutrophils 89 Respiratory chain 239

abnormalities 210 tissue-specific isoforms of enzymes 212

Respiratory control ratio (RCR) 353 Retroposons 222 Retropseudogenes 223 Ros 15 RTK

overexpression 14 signal transduction 15

Salla disease 400 Sandhoff disease 383 Secretion of digestive enzymes

intracellular C a 2 + as a regulator 72 Sickle cells 57 Spectrin 61,64

abnormalities of molecule 65 hemolytic anemia 66 mutants 66

Sphingosine 90 Staurosporine 88,89

N-propan-2-ol- and N-phenyl-derivatives 88 Steinen disease 102 Storage diseases 379-394 Subacute necrotizing encephalomyelopathy

(Leigh's disease) 229 Substance Ρ 29 Sulfatide activator 386

in glycolipid catabolism 387 Superoxide dismutase 341

Tay-Sachs disease 383 T E M P O (2,2,6,6, tetramethylpiperidine-l-oxyl)

292 fluidity of human membranes 293

Thermogenesis 265 mechanism 267

Thermoregulation 265 Thrombin 31 Thyroid hormone 268 T L C K (N-tosyl-L-lysine chloromethvl ketone)

88 Trifluoperazine 88 Trolox 91 Tumor promotion 89

activation of protein kinase C 84 Tyrosine kinase 32

activated in human tumors 44

Ubiquinone-cytochrome c oxidoreductase (complex I I I ) 216

Uncoupling protein 259, 266 as dimer 267 G D P binding 274 latent form 272 long-term regulation 272 masking-unmasking 272 mRNA-synthesis 275

Unsaturated fatty acids 289

V-fes 46 V-src 46 Viral oncogenes 14 Vitamin C

antioxidant, anticancer, anti-aging effects 338

Vitamin Ε 90, 338 anticancer, anti-aging effects 338 antioxidant role 90, 338 differentiation in human neuroblastoma 90 H 2 0 2 production inhibition in human

neutrophils 90 in plasma 91

platelet anti-aggregation agent 90

X-linked adrenodystrophy 411

Zellweger syndrome 411,420