The Possible Role of Glycoproteins in Neural Function

BRIEF PROPOSALS THE POSSIBLE ROLE OF GLYCOPROTEINS IN NEURAL FUNCTION ERIC G. BRUNNGRABER, Ph.D.* The structural complexity ofa protein is determined by die sequence ofamino acids in the peptide chains of which it is composed and by the geometrical arrangement of these chains in three-dimensional space. Glycoproteins characteristically contain carbohydrate chains; these are attached at various points along die polypeptide chains. The inherent complexity of the carbohydrate portion of the glycoprotein molecule causes a manifold increase ofthe complexity ofdie totalstructure. The sugars that commonlyform a part ofdiese polysaccharide chains include N-acetylneuraminic acid, fucose, galactose, mannose, glucosamine, and galactosamine. It is possible to have a linearsequence ofsugars that form repeating units consisting ofhexosamine and hexose. It is also possible to have highly branched polysaccharides. Furthermore, the chains may be quite small or as large as a small proteinmolecule. N-acetylneuraminic acid and fucose, ifpresent, are invariably glycosidically linked as terminal groups. These two sugars possess unique properties. Fucose contains a mediyl group, endowing die molecule widi a lipophilic group not present inothersugars. N-acetylneuraminic acid contains acarboxyl group, endowing die molecule with a negative charge. The possible variations in the structure of the polysaccharide chains seem almost infinite, aldiough future research will doubtless provide some measure oforder in the number ofchain types that nature has devised. Brain tissue contains a minimum of nine chain types diat differ in molecular size, charge, and sugar composition. Future separation methods will undoubtedly uncover a much larger number ofchain types. A single glycoprotein molecule may contain more than one polysaccharide chain, and die number and chemical characteristics ofthe many polysaccharide chains attached to die protein molecule allow for many possible macromolecular structures. The inherent polymorphism of the glycoprotein molecule—the many possible permutations and combinations in the location, chemical structure, and configuration ofthe polysaccharide side chains—suggests that the glycoprotein molecule is a reasonable candidate for future investigations designed to elucidate macromolecular alterations due to functional activity in the central nervous system. Brain tissue contains a high concentration ofglycoproteins. It can be calculated that as much as 5-15 per cent ofdie total protein content ofthis tissue may consist ofglycoprotein . But much more important is the finding that most ofthese glycoproteins are mem- * Illinois State Psychiatric Institute, 1601 West Taylor Street, Chicago, Illinois 60612. 467 brane bound. Strenuous homogenization of die tissue widi the purpose of obtaining glycoproteins in soluble form can extract only 20-30 per cent ofdie total glycoprotein of brain tissue. The rest remains bound to die lipid-rich residue. Analysis ofnerve endings, axonal fragments, and other membranous structures, obtained by density-gradient centrifugation of brain tissue diat had been homogenized under controlled conditions, has revealed the close association ofglycoproteins with such structures. The synaptic region, through which impulses must pass in order to continue dieirjourney from cell to neighboring cell, contains a high concentration ofmembrane-bound glycoproteins. So do die axons and the fragments diat are derived from other membranes ofthe neuron and glia cell. Glycoproteins are not conspicuous in the cytoplasm. The results ofsubcellular fractionation studies are readily reconcilable with the observations of histochemists, who uniformly find that carbohydrate-rich material fills the spaces between adjacent nerve cells and is especially concentrated in die synaptic regions. In general, glycoproteins are present in high concentration in extracellular fluids. Glycoproteins are also important structural components of die plasma membrane of a wide variety ofcell types. Apparently these substances are synthesized within die cell in ordertoperform an extracellular function. In some cases the secreted glycoprotein functions at locations remote from the site ofsyndiesis. In other cases the secreted glycoprotein appears to function at die cell surface or in die intercellular space immediately adjacent to the parent cell, thereby playing a role in the relationship of die cell and its immediate environment. Most secreted proteins are glycoproteins, while most intracellular proteins are not. It appears diat brain glycoproteins are not an exception. Although synthesized in the nerve cell body, probably in the Golgi region, diey migrate to the cell surface. During this migration, additional sugar residues may be added to die molecule. Secretion appears to be limited to a process in which the glycoprotein becomes deposited upon the outer portion ofdie...