Involvement of glycolipid-enriched domains in the transduction mechanism of neurotrophins in...

Bioscience Reports, Vol. 19, No. 5, 1999

MINI REVIEW

Involvement of Glycolipid-Enriched Domains in theTransduction Mechanism of Neurotrophinsin Cultured Neurons

P. Palestini,1 M. Masserini,1,5 G. Bottiroli,2 J. Brunner,3 T. Mutoh,4 A. Ferraretto,1

D. Ravasi,1 and M. Pitto1

Specialized domains, displaying a peculiar lipid and protein composition, are present withinthe plasma membrane of mammalian cells and play a pivotal role in fundamental mem-brane-associated events. Among lipids, sphingolipids (in particular glycolipids and sphingo-myelin) are characteristically enriched within such domains. Moreover, a series offunctionally related proteins is present, suggesting the involvement of these membranestructures in the mechanism of signal transduction and lipid/protein sorting. An increasingbody of evidence suggests that domains are dynamic structures, and that their dynamicfluctuations can modulate the activity of domain-associated proteins through changes ofglycolipid-protein interaction. Even if a large body of experimental investigation has beencarried out on eukaryotic cells, only little attention has been paid to the neuron. The pur-pose of the present review is to summarize the observations implying a functional role ofglycolipid-enriched domains in cultured rat cerebellar granule cells.

KEY WORDS: Glycolipid-enriched domains; signal transduction; cerebellar granule cells;gangliosides; TrkB.

ABBREVIATIONS: BDNF, brain-derived neurotrophic factor; CTB, cholera toxin Bsubunit; ECL, enhanced chemiluminescence; E/M, pyrene excimer to monomerfluorescence intensity ratio; GED, glycolipid-enriched domains; HRP, Horse RadishPeroxidase; NT, Neurotrophins; PKC, protein kinase C; PMA, phorbol 12 myristate-13acetate; Trk, tyrosine kinase; TrkB, brain-derived neurotrophic factor tyrosine kinasereceptor; TyrP, phosphotyrosine; VCS, Vibrio Cholerae sialidase; [125I]TID-GM1,9-[[[2-(125I)iodo-4-((trifluoromethyl)-3H-diazirin-3-l)benzyl]oxy]carbonyl]nonanoyl-GM1ganglioside.

INTRODUCTION

Singer and Nicholson (1972), predicted the presence in biological membranes ofdomains, that is of zones where the concentrations of given components and thephysicochemical properties are different from the surrounding environment. Later

1Department of Medical Chemistry and Biochemistry, Medical School, University of Milano-Bicocca,Via Saldini 50, 20133 Milano, Italy; E-mail: [email protected]

2Hystochemistry Center, C.N.R., Pavia, Italy.3E.T.H., Zurich, Switzerland.42nd Department of Internal Medicine, Fukui University Faculty of Medicine, 910-1193 Fukui, Japan.5To whom correspondence should be addressed.

3850144-8463/99/1000-0385$l6.00/0 © 1999 Plenum Publishing Corporation

386 Palestini et al.

on, the validity of this hypothesis was demonstrated by several investigations, thatascertained the presence and the biological role of macro- and micro-domains ineither artificial or cellular models, using a variety of techniques (Thompson andTillack, 1985; Masserini et al., 1989; Tocanne et al., 1989; Welti and Glaser, 1994;Palestini et al., 1994; Terzaghi et al., 1994). A simplified approach to investigate thissubject was introduced by a procedure believed to be able to isolate membranedomains on the basis of their insolubility in cold nonionic detergents (Kurzchalia etal., 1995; Parton and Simons, 1995). It has been shown that membrane fractionsprepared by these techniques are peculiarly enriched in cholesterol, sphingomyelinand in glycolipids (glycolipid-enriched domains, GED) (Brown and Rose, 1992;Cinek and Horejsi, 1992; Sargiacomo et al., 1993). Among glycolipids, GED areenriched in GM1 ganglioside, which is often used as a lipid marker of these struc-tures (Anderson, 1993; Parton, 1994; Wu et al., 1997).

The peculiar lipid composition of GED, also detected in apical membranes ofpolarized cells, suggested their particular role at the Trans Golgi Network (TGN)level, in the context of a generic involvement of these domains in the mechanism oflipid/protein sorting in all cell membranes (Simons and Van Meer, 1988).

GED are peculiarly enriched in several proteins. Among these, GPI-anchoredproteins, tyrosine kinase receptors, mono- and heterotrimeric G proteins, Src-liketyrosine kinases, protein kinase C isoenzymes, and others (Brown and Rose, 1992;Lisanti et al., 1994; Hope and Pike, 1996; Wu et al., 1997). The observed presenceof functionally related molecules and a growing body of experimental evidence sug-gests a key role of glycolipid domains in the mechanism of signal transduction(Simons and Ikonen, 1997).

OPEN QUESTIONS ABOUT GED

Many issues concerning the biological role of GED are still not completelyunderstood. For instance, is the formation of domains subjected to modulation byspecific signals at the level of the plasma membrane? How does the modulation ofsignal transduction occur within domains? A key role in GED is surely played byinteraction among domain components. It is known that glycolipids are interactingwith glycoproteins (Terzaghi et al., 1993), and with each other (Thompson and Til-lack, 1985; Ferraretto et al., 1997); in caveolae (glycolipid-enriched invaginations ofthe plasma membrane found in many mammalian cells) GM1 interacts with theprotein VIP21/caveolin (Fra et al., 1995; Simons and Ikonen, 1997); cholesterolinteracts with VIP21/caveolin and with porin, another protein found in domains(De Pinto et al., 1989; Murata et al., 1995). Even if a large body of experimentalinvestigation has been carried out on eukaryotic cells, only little attention has beenpaid to the neuron. The purpose of the present review is to summarize the obser-vations implying a functional role of glycolipid-enriched domains in cultured ratcerebellar granule cells.

NEUROTROPHINS AND GANGLIOSIDES

Among the molecules whose mutual interaction is presumably important forthe physiological functions of the nervous system are gangliosides and neurotrophin

Glycolopid-Enriched Domains in Neurons 387

receptors. Neurotrophins (NT), are polypeptides that promote differentiation andsurvival of both central and peripheral neurons. Molecules such as the brain-derivedneurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3, and neur-otrophin-4/5 are part of this group. NT initiate signal transduction inducing thedimerization and the activation of a receptor tyrosine kinase of the Trk family(Ferrari and Greene, 1996).

Gangliosides, glycosphingolipids located on the outer layer of the plasma mem-brane, expose their oligosaccharide moiety toward the external medium, supplyingthe cell with a variety of recognition sites. In fact, they have been reported to behaveas receptors for a number of external ligands, thus implicating their involvement ina series of functions including signal transduction across the plasma membrane(Brady and Fishman, 1979; Cheresh et al., 1986; Hakomori, 1990; Claro et al., 1991;Masserini et al., 1992; Tettamanti and Riboni, 1993).

The existence of a relationship between gangliosides and NT receptors has beendocumented (for a review of the argument see Lindsay, 1996). A first line of evidenceconcerns the capacity of exogeneous gangliosides to increase the life span of neuronscultured in vitro (Lindsay, 1996). A second line of evidence concerns the capacity ofexogenously added gangliosides to enhance NT action (Lindsay, 1996). Moreover,it has been reported that GM1 gagliosides interacts with the NGF receptor (Mutohet al., 1995; Mutoh et al., 1993) and that endogenous GM1 is co-localized with theBDNF receptor in neuronal membrane domains (Wu et al., 1997). Therefore, thehypothesis that interactions among NT receptors and gangliosides play a role inphysiological functions and in pathological events of the nervous system deserves tobe evaluated. Starting from the assumption of a relationship between GM1 ganglio-side and TrkB, the BDNF receptor, we carried out investigations with the aim toassess: (1) whether GM1 and TrkB are colocalized within specialized domains of theplasma membrane; (2) how their mutual interaction can affect the receptor activity.

In order to choose a neuronal study model to investigate the above mentionedissues, we focused on rat cerebellar granule cells, for a series of reasons: first, theyexhibit good resistance in culture; second, they express both GM1 and TrkB (Nono-mura et al., 1996; Palestini et al., 1998); third, the pattern and metabolism ofendogenous gangliosides in these cells, along with the effects exerted by glutamate,have been extensively investigated. (Riboni et al., 1990; Eboli et al., 1993).

GED IN CEREBELLAR GRANULE CELLS

The first report of glycolipid-enriched domains in brain cells coincides with theobservation that gangliosides are concentrated in the synaptic regions of neurons(Hansson et al., 1977). Moreover, it has been reported (Palestini et al., 1991) thatGD1a molecular species having different lipid moieties are not randomly distributedin microsomal membranes prepared from rabbit brain, thus supposing their segre-gation into domains. However, as regarding cerebellar granule cells, no informationwas available. In order to detect the presence of GED in these cells, we set up a newfluorescence ratio imaging technique based upon the use of a fluorescent pyrene-derivative of GM1 ganglioside.


Pyrene-labeled lipids are particularly suitable for monitoring the aggregation stateof labeled molecules, since the spectroscopic features of molecules that do not inter-act with each other (monomers, M) are quite different from that of interacting ones(excited dimers or excimers, E) (Galla and Hartmann, 1980). High values of the E/M intensity ratio are indicative of high probability of pyrene collision and directlyrelated to the lateral phase separation extent of labeled molecules. Therefore, theexcimer formation technique of pyrene-labeled lipids coupled to fluorescence digitalimaging microscopy, by directly visualizing the E/M ratio values, allows the studyof domain formation and of their dynamics. For this purpose we synthesized afluorescent derivative of ganglioside GM1 (pyrene-GM1), bearing a pyrenedode-canoyl-residue in substitution of the native fatty acid present on the ceramide moiety(Pagano et al., 1989) (Figs. 1, 2). The imaging results showed that pyrene-GM1 isdistributed in domains within the cell plasma membrane of cerebellar granule cells,with a concentration significantly higher in neuritic processes than in cell bodies(Terzaghi et al., 1994).

In order to assess the presence of TrkB in GED of granule cells, we performedan experiment with the aim of isolating GED from these cells. For this purpose, weapplied a technique widely used for the isolation of such domains from a variety ofcells, based on their resistance to treatment with cold nonionic detergents. Aftersuch treatment, the cell lysate was submitted to discontinuous sucrose gradient cen-trifugation. The fraction collected at the boundary between 5 and 30% sucroseshowed a strong enrichment of both GM1 and TrkB receptor, indicating that thesemolecules are concentrated within specialized domains of the plasma membrane ofcerebellar granule cells (Fig. 3).

Fig. 2. Technique of excimer formation imaging.

Fig. 1. Structure of pyrene-GM 1 ganglioside.


Fig. 3. Assessment of the amount of TrkB and GM1 gangliosidein Triton-resistant domains prepared from rat cerebellar granulecells. Cells were treated with Triton X-100 (1%, 30 min, 4°C) andthen submitted to ultracentrifugation (250,000 x g, 20 hr) in a dis-continuous sucrose gradient. One-ml fractions from the gradientwere each treated with TCA and the precipitates were submitted to7% SDS-PAGE and transferred to PVDF membranes. Membraneswere blotted with anti-TrkB antibodies (panel A) and with Choleratoxin B subunit labeled with HRP (panel B), followed by enhancedchemiluminescence detection. Fraction n.4 corresponded to theinterface between 5 and 30% sucrose. The molecular weight ofTrkB (145 KDa) is indicated.

DYNAMICS OF GLYCOLIPID DOMAINS IN CEREBELLARGRANULE CELLS

It is known that exogenously administered gangliosides affect Trk activity(Mutoh et al., 1995). On the contrary, the influence of endogenous gangliosides,and in particular of dynamic changes of their local concentration in the receptorenvironment, on Trk activity, is unknown. One of the difficulties to overcome, ininvestigating the role of endogenous GM1 on TrkB activity, was to change the gang-lioside density in the membrane region around the receptor, without using exogen-ous glycolipid.

The dynamics of glycolipid domains has been only partially investigated in thepast. Nevertheless, different investigations showed that the segregation extent of


ganglioside can be affected by specific stimuli arriving at the plasma membrane: forinstance, an increase of Ca2+ concentration, or the presence of external ligand pro-teins (e.g. tetanus toxin or cholera toxin) (Tettamanti and Riboni, 1993, 1994). Inorder to follow the same issue within the frame of a signal transduction process, wedecided to induce a stimulus at the cytosolic face of the plasma membrane of cul-tured rat cerebellar granule cells, and monitored the occurrence of changes at theexoplasmic face. For this purpose, we induced activation of protein kinase C (PKC)and monitored changes of the accessibility of gangliosides to the membrane-imper-meant enzyme Vibrio Cholerae sialidase (VCS). Previous reports indicate that mem-brane gangliosides are not all equally accessible when analyzed for their reactivitywith various ligands (Ito et al., 1993; Stewart and Boggs, 1994; Macala and Yohe,1995). Their accessibility appears to be modulated by factors such as their structure(oligosaccharide and ceramide composition), their concentration within the mem-brane, their environment and also by the nature of the ligand (Iwamori et al., 1983;Lampio et al., 1984; Masserini et al., 1988; Palestini et al., 1994; Perillo et al., 1994).

Enzymes, sialidase included, have been previously used to monitor glycolipidexposure and accessibility at the membrane surface (Iwamori et al., 1989; Stewartand Boggs, 1994; Macala and Yohe, 1995). In particular, it has been shown that theactivity of Vibrio cholerae sialidase upon GD1a ganglioside is sensitive to the mem-brane surface density of this glycolipid (Venerando et al., 1982; Masserini et al.,1988; Palestini et al., 1991). More precisely, it has been shown that the susceptibilityof GD1 a to sialidase decreases, when its segregation into domains increases.

Under the standardized conditions that were set up (Palestini et al., 1991), VCSpartially affected gangliosides of intact living cerebellar granule cells, being GT1band GD1 a hydrolyzed with formation of the respective products, GD1b and GM1.Then, we followed the effect of the addition of the neurotransmitter glutamate.Addition of toxic doses of glutamate to rat cerebellar granule cells triggers a seriesof events leading to cell death. It is believed that this is due to the overstimulationof the glutamate receptor, inducing an influx of Ca2+ from the external medium,followed by the irreversible translocation of protein kinase C (PKC) (Eboli et al.,1993).

Experiments have been carried out in various conditions leading to PKC acti-vation (addition of phorbol esters or glutamate), or to PKC inhibition (addition ofglutamate in the absence of Ca2+ in the medium, or addition of staurosporine). Theresults showed that, while the mere binding of glutamate has no effect on gangliosidedistribution within the plasma membrane, the translocation and activation of PKCis followed by an increase of ganglioside domains formation (Fig. 4). These dataindicate that a signal at the cytoplasmic side of the plasma membrane can be trans-duced to the exoplasmic face as a change in the segregation state of glycolipids(Palestini et al., 1998).

MODULATION OF GLYCOLIPID–PROTEIN INTERACTION IN GED

As a further step, we decided to investigate whether the activation of PKC isable to affect ganglioside-protein interaction. We investigated this subject utilizingthe photoactivable, radioactive derivative of GM1 ganglioside, [125I]TID-GM1.


Fig. 4. Exposure of gangliosides GD1a and GT1b at the plasma membrane surface of culturedcerebellar granule cells probed with Vibrio Cholerae sialidase, under different conditions leadingto inhibition (–) or activation ( + ) of protein kinase C (PKC) translocation and activation.PMA = phorbol-2 myristate-5 acetate; STAU = staurosporine. The values are the mean ± SD offour experiments. Statistical significance (t-test) against the control: * =p<0.05; ** =p<0.01.

After incubation of [125I]TID-GM1 with cells and photoactivation, cells were submit-ted to 2D electrophoresis followed by autoradiography. A few proteins were prefer-entially crosslinked by the ganglioside, becoming radiolabeled, including a proteinof about 92 KDa and pl of about 4. After treatment with PMA (phorbol-2 myristate-5 acetate), this radiolabeled protein was no more detectable. In the meanwhile,another protein of about 15 KDa of MW and pl of 6.5, previously not detectable,was crosslinked by [125]TID-GM1 (Masserini et al., 1998).

These data show that PKC translocation from the cytosol to the endoplasmicside of the membrane affects ganglioside-protein interaction at the outside of theplasma membrane.

MODULATION OF RECEPTOR ACTIVITY IN GED

In the light of the above observations, we decided to investigate whether thechange of ganglioside distribution in the outer layer of the plasma membrane ofcerebellar granule cells, inducible by a pulse of glutamate or phorebolester, was ableto affect also the activity of TrkB, the receptor of BDNF.

Our approach consisted in monitoring tyrosine phosphorylation state of thereceptor, and the content of GM1 ganglioside, present in the immunoprecipitatesobtained with anti-TrkB antibodies from cells after different treatments. Given their


colocalization in GED, the co-precipitation of GM1 ganglioside with TrkB wasexpected, since antibodies directed against TrkB likely cause the receptor to precipi-tate together with its glycolipid environment. Moreover, there have been reports ofthe occurrence of a tight association between GM1 and Trk receptors (Mutoh et al.,1995).

First, we employed short-term incubation with PMA. Upon PMA treatment,the amount of GM1 ganglioside which co-precipitated with the receptor decreasedwith respect to control, untreated cells, indicating a decrease in its local densityaround TrkB. This suggests that PMA elicits a redistribution of ganglioside withinthe plasma membrane, displacing it from the TrkB environment. More interestingly,the decrease of ganglioside associated to TrkB was paralleled by a concomitantdecrease of the tyrosine phosphorylation of the receptor. More strikingly, underthese experimental conditions the addition of BDNF was no longer able to stimulatethe strong phosphorylation of the receptor, normally exerted by this ligand (Pitto etal., 1998).

The observed PMA-induced decrease of TrkB tyrosine phosphorylation wasnot due to the proteolytic degradation of the protein. Moreover, a kinase assaycarried out with radioactive ATP on immunocomplexes obtained from control andfrom PMA-treated cells, showed a decrease of TrkB phosphorylation in PMA-treated cells with respect to control, comparable to the decrease of tyrosine phos-phorylation detected with anti-tyrosine phosphate (TyrP) antibodies. This resultrules out also the possibility of a phosphorylation of TrkB serine or threonine resi-dues exerted by PKC, and a possible consequent down-regulation of receptor phos-phorylation. All the preceding observations open the interesting possibility that adecrease of GM1 ganglioside molecules in the membrane area surrounding TrkB,induced by PKC activation, is responsible for the decrease in receptor activity, eitherin basal condition or when stimulated by BDNF. This may prevent receptor dimeriz-ation. It is interesting to remember that an opposite change (increase) of GM1 con-centration in the plasma membrane, obtained by addition of exogenous ganglioside,induces an increase in Trk activity, and rescues neuronal cells from apoptotic death,at least in part by evoking Trk receptor dimerization and autophosphorylation (Fer-rari et al., 1995). It is also worth noting that BDNF is able to evoke PKC activation(Zirrgiebel et al., 1995), thus opening the possibility of a mechanism for receptordown-regulation.

Moreover, the observation that the change of ganglioside association with thereceptor is consequent to PKC activation, suggests a possible correlation betweenreceptor modulation and trans-membrane signaling.

CONCLUDING REMARKS

A conceivable picture, inferred from the data obtained on cerebellar granulecells, is that following PKC activation, a central event in inward-directed transduc-tion, cell may dispatch outward-directed messages to glycolipids of the plasma mem-brane outer layer, changing their segregation state and therefore modulatingreceptor activity through dynamic changes of the lipidic environment. The overall


Fig. 5. Effect of endogenous GM1 ganglioside distribution on the activity of TrkB, receptorof the brain-derived neurotrophic factor (BDNF), in rat cerebellar granule cells. In cerebel-lar granule cells TkrB is normally associated with glycolipid-enriched domains present inthe plasma membrane (1). The addition of phorbol-2 myristate-5 acetate (PMA), or of theneurotransmitter glutamate in cytotoxic dose (100mM), to cells, induces translocation andactivation of protein kinase C, a typical intracellular event of transmembrane signal trans-duction, classically exerting intracellular responses. As an alternative pathway, cell dis-patches outbound by changing glycolipid segregation, that increases, at the explasmic faceof the plasma membrane (2). Following this change, the pattern of proteins, and in particu-lar the amount of TrkB associated to the glycolipid domains, varies (3). The activity of thereceptor, when the ganglioside concentration in the receptor environment is lowered,decreases with respect to control (3). Under these conditions, BDNF is no more able toenhance TrkB receptor tyrosine phosphorylation activity, as it normally does (4).

hypothesis that we propose is summarized in Fig. 5, suggesting that dynamic changesof endogenous glycolipids in the environment of a receptor can affect its activity.This correlation introduces new concepts into the comprehension of biochemicalphenomena involved in physiological functions of the nervous system and in neuro-degenerative disorders. However, this hypothesis is drawn on the basis of investi-gations carried out on this particular neuronal model system, and the number ofinvestigations concerning the biological role of GED in neurons is still limited.Therefore, several points need still to be clarified.

For instance, it is not known if the mechanism proposed can be extended toother neuronal cells. In favor of this possibility lies the evidence that membranedomains are present in other cell types such as neuroblastoma cells and hippocampalneurons (Gorodinsky and Harris, 1995; Ledesma et al., 1998).

Another open issue is whether or not the processes above described can occurin vivo. Also in this case, it could be said that the existence of GED, and even theirenrichment in TrkB, has been demonstrated in brain (Olive et al., 1995; Wu et al.,1997). It is possible to further speculate that this mechanism should be more active


in embryonal cells, which are more responsive to neurotrophic factors. Of course,the evaluation of these hypotheses deserves experimental work.

Finally, an implication of this model is possible for human diseases, such asischaemia and trauma, and in neurolipidoses. In fact, excitotoxic mechanisms dueto abnormal glutamate release have a well established role in the pathogenesis ofneuronal injury following acute CNS such as ischaemia and trauma (McCulloch,1992).

On the other side, the involvement of GED is hypothesizable in neurolipidosessuch as GM2 gangliosidosis, in which pathological increases of glycolipids areobserved, besides lysosomes, in the Golgi apparatus and plasma membrane (Sonder-feld et al., 1985). As a direct consequence of changes in their local concentrationone can expect influences at the level of GED, present in both the above mentionedcell compartments. It can be speculated that these changes could affect neural func-tion and interfere with correct signal transduction, thus contributing to the patho-genesis of these disorders.

ACKNOWLEDGEMENTS

The research presented in this review was supported in part by a grant fromM.U.R.S.T. (Rome, Cofinanziamento 1998).

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