P. Cuatrecasas – författare

This new se ries is concerned with intercellular communication and recognition. It is now widely appreciated that these processes playa crucial role in virtually all biological systems and functions. These encompass fertilisation, embryonic development, infectious interactions, the activity of the nervous system, the regulation of growth and develop­ ment by hormones and the immune response to foreign or 'non-self antigens. Historically as described in the first review in this volume, the general concept of cell-associated receptors as the molecular entity primarily responsible for the specificity of signal recognition arose independently in the fields of immunology, pharmacology and developmental biology. From an early stage the analogy between cellular recognition and the discriminatory activity of antibodies and enzymes was emphasised. A vital conceptual advance, expressed most c1early by Linus Pauling and Paul Weiss, was the idea that non-covalent molecular interactions (of proteins in particular) were responsible forbiological specificity in in general. In the last decade several major advances have led to a new level of understanding of the molecular basis of cellular recognition. In several systems (in particular with neurotransmitters, hormones and antigens) it is possible to direct1y demonstrate the existence of receptors - associated in each case with the cell surface. These studies have been paralleled by equally important insights into the general structure and organisation of cell membranes and the possible ways in which signals arriving from the 'outside' can be transduced across the cell surface membrane to induce or regulate the cell's programmed responses.

This new se ries is concerned with intercellular communication and recognition. It is now widely appreciated that these processes playa crucial role in virtually all biological systems and functions. These encompass fertilisation, embryonic development, infectious interactions, the activity of the nervous system, the regulation of growth and develop­ ment by hormones and the immune response to foreign or ''non-self antigens. Historically as described in the first review in this volume, the general concept of cell-associated receptors as the molecular entity primarily responsible for the specificity of signal recognition arose independently in the fields of immunology, pharmacology and developmental biology. From an early stage the analogy between cellular recognition and the discriminatory activity of antibodies and enzymes was emphasised. A vital conceptual advance, expressed most c1early by Linus Pauling and Paul Weiss, was the idea that non-covalent molecular interactions (of proteins in particular) were responsible forbiological specificity in in general. In the last decade several major advances have led to a new level of understanding of the molecular basis of cellular recognition. In several systems (in particular with neurotransmitters, hormones and antigens) it is possible to direct1y demonstrate the existence of receptors - associated in each case with the cell surface. These studies have been paralleled by equally important insights into the general structure and organisation of cell membranes and the possible ways in which signals arriving from the ''outside'' can be transduced across the cell surface membrane to induce or regulate the cell''s programmed responses.

Hardly a decade ago, membrane receptors were an attractive but largely unproven concept. Since that time enormous progress has been made, and we are now able to consider receptors much more concretely. Their existence has been established, their binding properties have been determined, and in some cases, they have been highly purified and their physical-chemical properties studied. It is now even possible to visualize microscopically some receptors. This progress has resulted largely from the development of highly powerful methods. These methods are the subject of this volume. Although considerably diverse, different receptors share certain common pro­ perties, and common problems are encountered in their study. Consequently, a small number of techniques are particularly useful in studying different types of receptors. Thus, it makes sense to speak about membrane receptor methodology. A very apparent problem in the study of membrane receptors is their presence in exceedingly small quantities and in a highly impure state. Therefore, very sensitive and specific techniques are required for their detection, characterization and purification. Such sensitivity and specificity is provided by the ability of receptors to bind certain ligands with very high affmity, and it is not surprising that most of the methods described in this volume depend upon this high affinity binding. The antigen-antibody interaction is of comparable sensitivity and speci­ ficity. Recently, a number of anti-receptor antibodies have been produced or found to occur spontaneously in auto-immune diseases. Undoubtedly, more will be produced in the future.

Hardly a decade ago, membrane receptors were an attractive but largely unproven concept. Since that time enormous progress has been made, and we are now able to consider receptors much more concretely. Their existence has been established, their binding properties have been determined, and in some cases, they have been highly purified and their physical-chemical properties studied. It is now even possible to visualize microscopically some receptors. This progress has resulted largely from the development of highly powerful methods. These methods are the subject of this volume. Although considerably diverse, different receptors share certain common pro­ perties, and common problems are encountered in their study. Consequently, a small number of techniques are particularly useful in studying different types of receptors. Thus, it makes sense to speak about membrane receptor methodology. A very apparent problem in the study of membrane receptors is their presence in exceedingly small quantities and in a highly impure state. Therefore, very sensitive and specific techniques are required for their detection, characterization and purification. Such sensitivity and specificity is provided by the ability of receptors to bind certain ligands with very high affmity, and it is not surprising that most of the methods described in this volume depend upon this high affinity binding. The antigen-antibody interaction is of comparable sensitivity and speci­ ficity. Recently, a number of anti-receptor antibodies have been produced or found to occur spontaneously in auto-immune diseases. Undoubtedly, more will be produced in the future.

This volume focuses exclusively on those endocytic processes that sequester proteins by a selective, receptor-mediated mechanism. In such an endocytic process, cell surface receptors specifically bind protein ligands and localize them to specialized invaginations of the plasma membrane. These regions are coated pits, so named because they are lined on the cytoplasmic face with an ordered array of the protein, clathrin. It is this ''coat'' which provides their characteristic electron microscopic image. Subsequently, these regions pinch off to form coated vesicles which rapidly lose their ''coat'' and then fuse with other organelles or the plasma membrane. The hallmarks of ,this process are the specific receptors, coated pits, coated vesicles and an ordered sequence of transit events leading to delivery to selected locations. Receptor recognition, specific disposition of the endocytosed ligand and the existence of recep­ tor-ligand complexes at highest density in coated pits define the process as selective and concentrative. This topic has received ever increasing attention during the past few years. The evolving mechanisms are especially exciting because they come at a time when the conventional views based on thermodynamic arguments suggest that proteins should not be able to cross into the cell. Receptor-mediated endocytosis, however, reconciles the view that biological membranes should be impervious to macromolecules with the evidence that certain mac­ romolecules do gain entrance into the cell. During the last few years this field has been stimulated by studies on the uptake and processing of low density lipoproteins (LDL) by cells.