Osmotic control of vasopressin release

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Osmotic control of vasopressln release Celia D. Sladek and William E. Armstrong Vasopresstn (anttdmrettc hormone) ts the primary regulator o] the osmolahty and volume of the extracellular fluM. Extracellular flmd osmolahty m turn ts one of the primary regulators of vasopressm release. Although this baste control system has been accepted for35 years, areas of controversy have existed relative to the location and characteristics of the mechamsms respons,ble for osmotic regulation of vasopressm release. In this arncle the promment features of these controversies wdl be discussed, and the compelhng evMence m favor of a complex osmorecepttve system with multiple components will be presented V a s o p r e s s l n (VP) release from the posterior pituitary IS regulated by a n u m b e r of variables including volume and o s m o l a h t y of the extracellular fluid (ECF) and blood pressure The osmolahty of the E C F is recognized as one of the most important determinants of V P release. VIa release m vtvo is exquisitely sensitive to fluctuatmns m E C F osmolality with a 1% increment in plasma osmolahty being sufficient to elevate plasma VP and a 2% increase being sufficient to cause a 2-3 fold increase in orculatlng VP levels ~ The initial evidence for a role of E C F o s m o l a h t y in the regulation of V P release and involvement of the hypothalamus in m o m t o n n g E C F osmolahty was presented by Verney 35 years ago 2, but investigations of the specific mechanisms involved in transducing a change in E C F osmolality into the appropriate change in the rate of VP release c o n t i n u e to this time Two Important issues relative to the mechamsms of the osmotic control of VP r e l e a s e h a v e b e e n a d d r e s s e d by n u m e r o u s m u l t i d i s o p l i n a r y studies( l ) W h a t is the nature of the receptor system which m o n i t o r s c h a n g e s in E C F osmolallty 9 and (2) W h e r e are these receptors located9 As the evid e n c e p e r t i n e n t to t h e s e issues is presented and chscussed in this review, it will b e e v i d e n t t h a t t h e s e are intertwining issues, because the locat i o n of t h e r e c e p t i v e e l e m e n t s is critical to interpreting studies designed to evaluate the receptor mechanisms. The nature of the receptor system Two types of receptors have been postulated in the osmotic regulation of V P release: o s m o r e c e p t o r s and sodium receptors Osmoreceptors were initially postulated by Verney 2 who demonstrated the ability of increases in both sucrose and sodium. but not glucose and urea, to stimulate ant]dluresls in dogs. Based on these o b s e r v a t i o n s It was suggested that effective osmotic agents were those 19~,5 Elmvler S~lence Pubhsher~ B V

molecules which were confined to the E C F either by virtue of their size (sucrose) or specific characteristics of the m e m b r a n e (sodium). Water would pass from the cell to the E C F as a consequence of the presence of these molecules m the E C F and result in a decrease in cell volume. The alteration in cell volume would then lmtlate the s u b s e q u e n t e v e n t s l e a d i n g to V P release_ In this paradigm the abihty of glucose and urea to cross the cell m e m b r a n e renders them lneffectwe osmotic agents. S u b s e q u e n t experim e n t s in dogs 3, s h e e p 4, g o a t s 5, monkeys 6 and humans 7 have confirmed t h a t vascular a d m i n i s t r a t i o n of hypertomc manmtol or sucrose solutions elicit VP release or antldiuresis, but glucose is ineffective and hypertonic urea is e i t h e r ineffective s or markedly less effective 4 than sucrose. Thus, evidence supporting an osmoreceptor mechanism has been obtained in several species. The sodium receptor hypothesis was formulated by Andersson 5 following observations that the effectiveness of various agents (sodium, sucrose and urea) in stimulating thirst or antldluresis was d i f f e r e n t w h e n they were infused into the cerebral ventricles than when given lntravascularly This c o u p l e d with t h e a s s u m p t i o n t h a t receptive elements located in the CNS must he behind the blood brain banner led him to conclude that the available data was incompatible with an osmor e c e p t o r m e c h a n i s m but consistent with a juxtaventncular sodium sensitive mechanism. Specifically, he observed stimulation of thirst and inhibition of water diuresls following lntracerebroventncular infusion of hypertonic saline, but dipsogemc and antidiuretic responses were inhibited rather than stimulated following ICV infusion of hypertonic sucrose He suggested that this inhibition was due to dilution of CSF sodium and therefore consistent with the juxtaventrlcular sodium r e c e p t o r h y p o t h e s i s .

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Furthermore, he suggested that the m t r a v a s c u l a r i n f u s i o n s of v a r i o u s hypertonlc solutions altered the CSF sodium concentration which was monitored by juxtaventricular sodium receptors and this in turn initiated the observed dlpsogenic and antldluretlc responses In an effort to evaluate the respective involvement and importance of osmoreceptors or CSF sodium receptors in the regulation of VP release° McKinley et al 9 performed an extensive series of experiments m which CSF sodium concentration was measured during lntracarotld or mtravent r l c u l a r a d m i n i s t r a t i o n of v a r i o u s h y p e r t o n l c s o l u t i o n s in c o n s c i o u s sheep In these experiments, it was demonstrated that CSF sodium concentratlon increased following mtracarotid infusion of hypertonlc saline, sucrose, and urea but not following hypertonlc glucose and galactose mfusions Of these solutions only the hypertonlc saline and sucrose elicited antldluresls Urea Induced only a weak antldluresls in spite of elicltmg the g r e a t e s t I n c r e a s e s in CSF s o d i u m ( + 7 mM Na) Thus, these observations indicate that osmotic regulation of VP release is not solely dependent of CSF sodium receptors and is compatible with the involvement of E C F osmor e c e p t o r s m t h e r e g u l a t i o n of V P release. However, other observations from McKinley's studies on the effects of intraventrlcular injections of hypertonic solutions do support a role for C S F s o d l u m r e c e p t o r s as well as osmoreceptors. Antidluresis was elicited by mtraventrlcular infusion of hypertonic saline, sucrose, and fructose (but not urea) if the osmotic agent was added m artificial CSF~ but a nonsaline hypertomc sucrose solution was ineffective McKinley et at 4 subsequently demonstrated that m t r a v e n t n cular infusion of sucrose In CSF actually decreased CSF, sodium concentration. When this decrease was counteracted by refusing sucrose m artificial C S F s u p p l e m e n t e d to 0 3 M NaCI, four of the s~x sheep exhibited drinking responses, but the response was significantly less than that observed following an i n f u s i o n of 0.45 MNaCI v, hlch should have caused a slightly smaller increase in CSF osmolahty These observations support the existence ot osmoreceptors, but also demonstrate a

167

T I N S - A p r d 1985

specific drinking response to increases in CSF sodium concentration which exceeds the response attributable to the osmotic properties of the NaCl alone. Thus, the direct m e a s u r e m e n t of CSF sodium in these studies provides clear evidence for the p a r t i o p a t l o n of osmoreceptors in the regulaUon of V P release These studies also support involvement of sodium receptors, but ~t should be noted that large changes in CSF sodium were reqmred to demonstrate sigmficant stimulation of water intake in these studies ( + 2 8 raM)4, and therefore, the sodium receptors are not responsible for the exquisite sensitivity of the V P system to increases in E C F osmolahty

Location of osmoreceptors In addition to provading the early evidence for osmoreceptors, Verney 2 also provided evidence that the osmoreceptive area which r e g u l a t e d V P release was located in the a n t e r i o r hypothalamus Subsequent studies utilizing electrolytic lesions c o n f i r m e d the importance of the region anterior to the ventral third ventricle ( A V 3 V ) m the osmotic regulation of V P release a n d d r i n k i n g l°_ R a t s w i t h A V 3 V lesions exhibited h y p e r n a t r e m i a and deflots in drinking and V P release to the hypernatremm. Goats with lesions m this s a m e r e g i o n also l a c k e d a s i g n i f i c a n t V P r e l e a s e to h y p e r n a t r e m i a 5 Thus, the A V 3 V region Is critical for lmtmting d n n k i n g and V P release in r e s p o n s e to elevation of E C F osmolality. As m e n t i o n e d previously, the location of the osmoreceptor or sodium receptor has been a central issue m interpreting the experiments designed to evaluate the osmoreceptor mechamsm T h e reason for this relates to the i m p o r t a n c e of the d i f f e r e n t i a l osmotic effectiveness of sucrose and urea to the hypothesis that the receptors are responding to changes in the osmolahty rather that the sodium c o n c e n t r a t i o n of the ECF. As discussed above, urea diffuses across cell m e m b r a n e s and therefore its presence in the E C F does not mltmte osmotically obligatory loss of water from cells However, the blood brain b a r n e r is i m p e r m e a b l e to urea and therefore, the presence of urea in the plasma should be an effective osmotic signal to an osmoreceptor located behind the blood brain barrier The location of the osmorecepttve region in the anterior hypothalamus suggested that the receptors would be affected by the

b l o o d b r a i n b a r r i e r H o w e v e r , the a n t e n o r hypothalamus region includes two areas which are devoid of a blood brain barrier the subfornlcal organ (SFO) and the o r g a n u m vasculosum of the lamina terminals (OVLT). Due to the absence of a blood brain barrier in these regions, they have been postulated to c o n t a i n the o s m o r e c e p t i v e elements 3,4, and additional investigations have addressed this possibility. Several types of evidence support a role for the O V L T m osmorecepUon. Electrolytic lesions of the O V L T in dogs attenuated the V P response to i n t r a v e n o u s i n f u s i o n of h y p e r t o m c sahne 4, and radio frequency lesions c o n f i n e d to t h e O V L T in s h e e p m a r k e d l y reduced the drinking response to hypertonic saline (VP release was not evaluated) 11 In b o t h of these studies there was evidence of residual osmosensitivlty following OVLT lesions In the sheep, damage of tissue dorsal to O V L T in addition to O V L T was r e q u i r e d to block the d n n k l n g response completely, and two of the dogs showed some VP response E v i d e n c e t h a t the O V L T region is critical for o s m o r e g u l a t i o n of V P release m rats comes from studies which demonstrated that hypot h a l a m o - n e u r o h y p o p h y s e a l explants p r e p a r e d from rats and maintained in organ culture retained the ability to increase V P release in response to mcreases in the osmolahty of the culture medium s Explants obtained from A V 3 V lesioned donors did not respond to osmotic stimulation 12_ These explants normally include only the ventral portion of the A V 3 V lesion (e.g the O V L T and a portion of ventral nucleus medianus which is immediately dorsal to the O V L T ) Therefore, the O V L T region appears to be necessary for maintaining normal osmoresponSlvlty of the V P system in rats, dogs, a n d sheep, but other osmoreceptwe regions must also exist to account for the residual responses observed. Evidence for an osmoreceptor function in the SFO ~s not as compelling as for the O V L T A V 3 V lesions do not include the SFO, but they do interrupt p r o l e c t ~ o n s f r o m t h e S F O to the nucleus medianus, O V L T , and V P neurons in the supraoptlc and parav e n t r i c u l a r nuclei T h e p r o j e c t i o n s from the SFO to supraoptlc neurons are predominantly excitatory 13 Therefore, i n t e r r u p t i o n of osmorecept~ve control m e c h a n i s m s from the SFO could be partially responsible for the abnormalities in water balance ob-

served following A V 3 V lesions. However, T h r a s h e r et al. ~4 were unable to d e m o n s t r a t e drinking deficits to h y p e r t o n i c saline infusions in dogs with SFO lesions, and investigators have been unsuccessful m demonstrating electrophyslologlcal activation of SFO neurons in rats following osmotic stimulation 15 although a population of O V L T units were excited by elevation of the superfusate osmolahty x6" In rats SFO lesions markedly attenuated the VP response to a subcutaneous injection of hypertomc saline 17, but the VP response to lntracerebroventncular lnlecUon of anglotensm II (Ref. 17) was also a t t e n u a t e d and t r a n s e c t i o n of SFO efferents compromised the antid i u r e t i c r e p o n s e to a c u t e h y p o volemla is Thus, selective removal of the excitatory SFO mnervatton of V P neurons may non-spectfacaily reduce the responsiveness of the system to other stimuli In conclusion, there is convincing evidence that the anterior p e n v e n t n c u l a r hypothalamus is critical for the osmotic regulation of fluid balance This location is consistent w i t h b o t h the d a t a i n d i c a t i v e of hypothalm~c o s m o r e c e p t o r s located outside the blood brain b a r n e r which monitor the osmolahty of the E C F and with the evidence indicative of perlventncular sodium receptors monitoring CSF sodium concentration. Other hypothalamac regions wbach have been avidly investigated as a potential site of osmosensltwe mechamsms regulating VP release are the magnocellular nuclei. Verney 2 lmtially speculated that this was an attracUve possibility due to the presence of the V P neurons in these nuclei and also the inclusion of this region m the anterior hypothalamic region which he demonstrated c o n t a i n e d the o s m o r e c e p t l v e elements. Evidence supporting osmosens~tlvity of supraoptic neurons has been obtained from lntraceUular recordings of electrical actwity m these neurons utlhzmg techniques in vitro and extracellular recordings tn v t v o In urethane-anesthetized rats, the apphcatlon of minute volumes of hypertonlc sahne immediately adjacent to supraoptic neurons by microtap increased electrical actwtty of the neurons m a r e v e r s i b l e m a n n e r ~9 S~mllarly, in hypothalamtc slices from rats 19 and guinea pigs 2° osmotically stimulated activity has b e e n observed in spontaneously active n e u r o n s of the SON_ Intracellular recordings of neurons in these preparations d e m o n s t r a t e d an osmotically induced depolarization of

168 the neurons which renders them more not negate a role for osmotic depolarsensRtve to stimulatton by excitatory ization of the VP neurons in regulating n e u r o t r a n s m l t t e r s ~9,2°, This osmotic V P release The location of the V P depolarization was not o b s e r v e d in n e u r o n behind the blood brain barrier h l p p o c a m p a l or v e n t r o m e d i a l hypo- dtctates that the osmoreceptor mechthalamic neurons, and thus, is not a amsm intrinsic to these neurons would generalized characteristic of all neur- be m o n i t o r i n g a different compartons 2°_ It may result from suppression ment of the E C F than osmoreceptors in the circumventricular organs Similarof a K + conductance 2° F u r t h e r m o r e , the osmotically induced depolarization ly, pertventrtcular sodium receptors can be aclueved by increasing osmola- w o u l d b e m o n i t o r i n g t h e s o d i u m hty with either NaCl or mannltol, and concentration in the CSF rather than is present when synaptic transmission is the plasma This might be important b l o c k e d TM T h u s , t h e V P n e u r o n s u n d e r c e r t a m physiological circumthemselves possess specialized osmo- stances. For example, McKinley has d e m o n s t r a t e d that the change in CSF receptor mechanisms T h e evidence for multiple osmo- sodium concentration following perir e c e p t o r s (1 e c i r c u m v e n t r i c u l a r pheral infusion of hypertonlc sahne osmoreceptors, CSF Na receptors and occurs more slowly and is attenuated relative to plasma 4 It is likely that the the V P n e u r o n itself) n e c e s s i t a t e s discussion of the respective roles and E C F surrounding SON neurons is also relative importance of these various b u f f e r e d f r o m acute a l t e r a t i o n s tn mechanisms in the osmotic regulation peripheral E C F osmolality, but would of V P release As m e n t i o n e d previous- be effected by chronic alterations This ly, V P release in w v o is extremely would suggest that the osmoreceptor senslhve to changes m E C F osmola- role of the V P n e u r o n may be to hty A l t h o u g h osmotic depolarization maintain responsiveness of the system was observed with an increase of 8 to chrontc stimulation Perlventrlcular mosmols in the intracellular recording sodium receptors may functton simistudies on hypothalamic slices, larger larly or may represent a specific CNS changes in osmolahty (15--23 mosmols) sensor mechanism In a d d i t t o n to t h e e v i d e n c e for were required to elicit neuronal f i n n g These changes are large compared to multiple CNS osmoreceptors, there is those required for physiologically sig- also evidence supporting the erastence of p e r i p h e r a l o s m o r e c e p t o r s which nificant a l t e r a t i o n s in VP levels m regulate V P release The best evidence vtvo It is u n l i k e l y t h a t a loss of is for hepatic osmoreceptors Increases sensitivity has occurred in this mechin plasma V P occur following infusions anism due to the in v i t r o approaches of hypertomc saline Into the hepatic used, since organ cultured hypothaportal vein in conscious dogs 23 and l a m o - n e u r o h y p o p h y s e a l explants refollowmg superfuslon of the hepatic tain the capacaty to respond to increportal vein in anesthetized rats 24. The m e n t s m o s m o l a l i t y as s m a l l as 5 mosmol/kg H 2 0 with a significant V P r e s p o n s e was o b s e r v e d m the absence of significant changes in sysincrease in h o r m o n e r e l e a s e 21 Furtemic plasma osmolality ,n both studthermore, usmg perfused hypothalamlc explants B o u r q u e and R e n a u d 22 ies In the anesthetized rats, superd e m o n s t r a t e d that osmosensltivity is fuston of the portal vein with hypertonic sahne stimulated seven out of reduced in supraoptic neurons in the eight phasically firing antidromically a b s e n c e of s y n a p t t c t r a n s m i s s i o n identified supraopttc n~urons and T h u s , it is u n l i k e l y t h a t o s m o t i c eight out of twenty-four continuously depolarization of the V P n e u r o n is the firing s u p r a o p t m n e u r o n s r e c o r d e d sole m e c h a n i s m responsible for osextracellularly 24 Vagal transection 23 motic regulation of VP release m v i v o blocked the VP response to osmotic F u r t h e r m o r e , the c o m p e l l i n g argustimulation of the hepatic osmorecepments for osmoreceptive mechanisms tor indicating that the V P response is located outside the blood brain barneurally m e d i a t e d . T h e h y p e r t o n i c rier, and the selective disruption of s a l i n e l u f u s l o n s in the conscious dogs osmoregulation of V P release followincreased hepatic portal vein osmolaing lesions of the O V L T both in mtact hty 9-14 mosmol/kg H 2 0 (Ref 23). animals a n d in h y p o t h a l a m o - n e u r o Thus, a 5-10% increase m portal hypophyseal explants supports an tmvenous osmolality was achieved. Ltard p o r t a n t role for osmoreceptlve eleet al_ 25 were unable to demonstrate ments extraneous to the V P neurons in stimulation of V P release following the regulation of V P release This does

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hypertonlc saline infusions into the portal vein of conscious dogs which resulted in increases of less than 5% m hepatic plasma osmolahty l'hus, hepatic osmoreceptors capable of stm~ulatlng VP release have been demonstrated, but they are less sensttive to changes m osmolahty than the hypot h a l a m l c osmoreceptor~_ H o w e v e r , their location is approprtate to inmate a response to gastric osmotic challenges and t h e i r s e n s i t i v i t y r a n g e appears appropriate for this, because h e p a t t c p o r t a l vein o s m o l a h t y mcreased by 5-10% following a meal 23 Thus, these receptors appear to represent another mechanism defending against changes m E C F osmolahty In conclusion, there ts compelling evidence for multiple osmoreceptlve elements mvolved in the regulation of VP release The location and specific charactenstics of these vanous osmorecepttve elements provide a regulatory system which can monitor and subsequently respond to osmotic alt e r a t i o n s in various fluid c o m p a r t ments in the body as well as a system which is exquisitely senslnve to small, short term stlmuh, but which retams responsiveness to chronic alterations m E C F osmolality Selected references l Dunn, F L,Brennan, T J,Nelson, A E and Robertson, G L (1973)J Chn Invest

52, 3212-3219 2 Verney, E B (1947)Proc R Aoc (London) 135, 25-106 3 Ramsay, D J , Thrasher, T N and Ked, L C (1983)Prog Brain Res 60, 91-98 4 McKinley, M J , Denton, D A and Welsmger, R S (1978) Brain Re~ 141, 89103 5 Andersson, B (1977)Ann Rev Physlol 30, 185-200 6 Swamlnathan, S (1980)J Phys~ol 307, 7183 7 Zerbe, R L and Roberts,on, G L (1983) A m J Physlol 244, E607-614 8 Sladek, C D and Kmgge. K M (1977) Endocrinology 101. 1834-1838 9 MeKanley, M J, Denton, D A , Leksell, L , Tarjan, E and Wemmger, R S (1980) Phystol Behav 25,501-504 10 Johnson, A K (1982)Dev Neurosct 15, 277-298 It McKinley, M J . Denton. D A . Leksell, L G , Mouw, D R . Scoggms, B A . SmRh. M H , Welslnger, R S and Wright, R D (1982) Brain Res 236. 210-215 12 Sladek. C D and Johnson, A K (2983) Neuroendocnnology 37, 78--84 13 Sgro, S , Ferguson, A V and Renaud, L P Brain Res_ (1984) 303, 7-13 14 Thrasher, T N , Simpson, J 13 and Ramsay, D J (1982) Neuroendocrinology 35, 63-68

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T I N S - A p rd 1985 15 Buranarugsa, P and Hubbard, J I (1979) J Phystol 291,101-116 16 Nelson, D O and Graham, C A (1983) Soc Neuroso Abstr 9, 198 17 Mangmpane, M L , Thrasher, T N , Ked, L C., Simpson, J B and Ganong, W F (1984) Brain Res Bull 13, 43-48 18 Mlsehs, R R and Eng, R (1981) Soc Neurosct Abstr 7 , 6 3 8 19 Leng, G , Mason, W T and Dyer, R G

(1982) Neuroendocnnology 34, 75-82 20 Abe, H and Ogata, N (1982) J Phystol 327, 157-171 21 Sladek, C D , Blmr, M L and Ramsay, D J (1982) Endocnnology 111,599--607 22 Bourque, C W and Renaud, L P (1984) J Phystol 349, 631-642 23 Chwalbmska-Moneta, J (1979)Am J Phy$lol 236, E603--609 24 Baertschl, A J and Vallet, P G (1981)

Gangliosides

J Phys~ol 315,217-230 25 Llard, J F , Dolcl, W a n d Vallotton, M B (1984) Endocrinology 114,986-991

Ceha D Sladek and Wdham E Armstrong are at the Departments of Neurology and Anatomy, Umverstty of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, N Y 14642, USA

of the neuron

Robert Ledeen While gangliostdes appear to be ubiquitous m vertebrate cells, those o f the neuron are characterized by their unusually high concentration and structural complexity This has given rise to the concept o f neuron-specific function(s), apart from their phystologwal roles tn other cells Current views on metabolism, locahzaaon, transport and developmental changes o f neuronal gangl,ostdes are briefly summarized A large part o f current research is focused on the neuritogemc and neuronotrophic properties o f ganghosides, us exemplified in their abihty to mduce differentmtzon in some primary neuronal cultures and neuroblastoma cell hnes Exogenously admtmstered gangliostdes also function in vlvo to facthtate survival and repair o f damaged neurons m both the CNS and PNS Efforts are now directed toward elucidation o f the underlying molecular mechamsms and the relanon o f such 'exogenous' effects to the funcaoning o f endogenous ganghostdes normally present in the neuron

The n e u r o n doctrine proposed by R a m o n y Calal around the turn of the century provided a cellular perspective of the nervous system which led eventually to the biochemical characterization of individual cell types Ganghostdes were among the first substances to be postulated as neuronal constituents Klenk made this proposal upon observing their enrichment in gray matter, then known to be the locus of 'ganglienzellen' (neurons). He was basically correct m assoclatmg the bulk of gray matter gangliosides with that cell type, even though the concept of uniqueness was eventually discarded as ganghosldes were discovered not only in the other cells of brain but in extraneural tissues as well The efforts of many investigators have demonstrated their presence in numerous vertebrate tissues and body fluids - virtually every one that has been subjected to careful analysis Nevertheless, the concept of a special function related to the neuron has persisted, perhaps owing to their unusual qualitative and quantitative features within these ceils Gangliosides, defined as slahc a o d - c o n t a m m g glycosphmgohpids, account for an estimated 5-10% of total lipid in the neuronal plasma m e m b r a n e , or about 10--20% m the external half of that bdayer where they are concentrated 1 Th~s is an order of magnitude or more

above their concentration in other membranes and makes them primary contributors to the c a r b o h y d r a t e - n c h glycocalyx on the surface of the neuron The quahtatlve features of neuronal gangliosldes are equally distinctive, owing to the high proportion belongmg to the ganglio structural series (see below) Perhaps the most conwncmg indication of neuron-specific function is the fact that neurons uniquely

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respond to exogenous ganghosides with pronounced morphological changes characteristic of differentiation The discovery of this phenomenon, to be discussed later, has been a major factor m shaping current research In the ganghoslde field

Characteristics of neuronal gangliosides The four or five major ganghosldes of m a m m a h a n brain belong to the gangho family, characterized by the presence of N-acetylgalactosamme as the sugar attached to lactosylceramlde through a GaINAc(IM--~4)Gal hnkage (Fig_ 1) Gangliosldes, like glycohplds generally, are classified and named on the basis of their oligosaccharlde chains Ceramlde is the name given to the hydrophoblc unit which anchors the molecule in the m e m b r a n e These structural features render ganghosldes soluble in both water and organic solvents, a fact that has been exploited

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Cerambde Fig. 1. Structurer of the five malor ganghostdes of mammahan brain GMI, R t = R2 = H. GDIa, Rt = NeuAc, R2 = H, GDlb. R t = H, R2 = NeuAc, GTlb, R t = Re = NeuAc, GQlb, R: = NeaAc(28)NeuAc, R2 = NeuAc The ztg-zag hnes of ceramzde represent hydrocarbon chains Nomenclature ts that proposed by Svennerholm2 1985.Else'.aerSoenaePuhhshersB V , Amsterdam 0378- 5012./85/$0200