The study of hormone and drug receptors has become one of the most exciting and rapidly moving areas of biomedical research. Elucidation of receptor mechanisms and receptor structure has become the common goal of many scientists from diverse backgrounds. The rapid advances achieved have been due, in large part, to the concentrated effort of workers from a variety of disciplines including classical pharmacology, biochemistry, endocrinology, cell biology, genetics’ and molecular biology, among others.
Hormone and drug receptors appear to be of three major types, which may be classified by their cellular locations. Found in the plasma membranes of cells are the receptors for a wide variety of polypeptide hormones, catecholamines and a variety of neurotransmitters. Included within this group are those receptors coupled to the enzyme adenylate cyclase. The second group of receptors are the soluble cytoplasmic receptors for the steroid hormones. A third type of hormone receptor is the receptor for the thyroid hormones which appears to be confined to the nucleus. Not only may these different types of receptor be distinguished in terms of their cellular locations but also by their mechanisms of action. Thus, the plasma membrane receptors appear to function by triggering the release of second messengers such as cyclic AMP or calcium which then regulate a variety of cellular metabolic events. The soluble steroid receptors bind steroid hormones in the cytoplasm, become activated and then enter the nucleus where they alter transcription of the genome. The thyroid hormones bind directly to nuclear receptors and also seem to alter transcription.
The modern era of receptor research can be envisaged as beginning with the advent of successful direct radioligand binding studies which permitted a direct approach to the investigation of the receptors. Well-validated radioligand binding assays for the study of almost all the known receptors are currently available. A wide variety of high affinity, high specific radioactivity radioligands are available for the investigation of these receptors.
One of the most significant insights to develop from ligand binding studies of hormone and drug receptors is that the receptors, rather than representing static ‘receiving stations’ for hormonal signals, in fact are subject to very dynamic regulation. This dynamic regulation of receptor number and properties likely represents one of the most important mechanisms which have evolved for the control of tissue sensitivity to humoral and neurohumoral messages. The present volume attempts to distill the essence of recent research concerning ‘receptor regulation’. Several words about its organization are in order. First, this field is already so vast that an encyclopaedic approach is not feasible. Accordingly, representative areas of research have been reviewed which seem best to highlight the important principles which are emerging. The first section of the book contains three chapters dealing with receptors for the peptide ‘hormones’ insulin, epidermal growth factor and prolactin. The second section deals with receptors for the neurotransmitters, catecholamines and acetylcholine. The essays in these first two sections serve to underscore the complexity and multiplicity of mechanisms which may regulate receptor properties. Several interesting and important principles emerge. Hormones are found generally to regulate their own receptors. As first shown for the insulin receptors by Roth’s group there seems to be an inverse correlation between the ambient level of hormone or neurotransmitter and the density of receptors on cells. Thus, the higher the agonist concentration the lower the receptor concentration. This appears to function as a feedback mechanism to dampen cellular sensitivity to hormonal or drug action in the face of high concentrations of biologically active agents. In the case of the acetylcholine receptor it is found that chronic nerve stimulation also leads to a compensatory decrease in receptor number. Mechanisms by which hormones ‘down regulate’ their receptors seem complicated and as yet are not fully delineated. These apparently involve hormone promoted internalization of receptors and change! in the rates of receptor synthesis, as well as changes in the rates of receptor degradation. The receptors for prolactin and angiotensin appear to be exceptions, since these receptors are ‘up-regulated’ by the natural hormone. In some cases antagonists may lead to an opposite change in receptor number; thus high concentrations of antagonists up-regulate receptors, possibly leading to increased sensitivity to hormone or drug effect.
In addition to regulation by ‘homologous’ hormones, receptors appear also to be regulated by a wide variety of hormones with which they do not normally combine. For example, thyroid hormone seems to control receptors for the catecholamines and prolactin among others. Steroid hormones are found to control the concentrations and properties of a variety of receptors for hormones and neurotransmitters which are found in the plasma membranes. Such ‘heterologous’ regulation is apparently a very common pattern for regulating the number of receptors.
Cuatrecasas, P., & Greaves, M. F. (2013). Receptors and recognition. Springer.