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The Receptor Concept : A Continuing Evolution 326
2004
Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University School of Medicine, and Vanderbilt Kennedy Center for Research on Human Development, Nashville, Tennessee 37232 T review briefly summarizes the development of the receptor concept, the identification of receptors based first on biological response data and subsequently on radioligand binding properties, and the biological and physiological understandings that these approaches have made possible. The development of receptor characterization began with receptors that ultimately were discovered to mediate response by coupling to G-binding proteins, also known as G protein–coupled receptors (GPCRs). Consequently, many if not all of the examples in this overview will describe studies characterizing GPCRs in general, and adrenergic receptors in particular. The purpose of this review, however, is not a detailed chronological account of a huge literature, but rather an overview of the fundamental questio...
Molecular pharmacology, 2000
The quantitative comparison of the relative potency of agonists is a standard method of receptor and agonist classification. If agonist potency ratios do not correspond in two given tissues, this is used as presumptive data to conclude that the receptors in those two tissues are different. This article presents data to show that a single receptor can demonstrate varying agonist potency ratios in different host cells. These data are described in terms of the production of more than one agonist-selective receptor active state and the interaction of these different active states with multiple G proteins in the membrane to produce cellular response. Stable host human embryonic kidney 293 cells with enhanced quantities of the respective Galpha-protein were created. Wild-type and Galpha-subunit enriched cells were then transiently transfected with human calcitonin receptor type 2 (hCTR2). Binding did not detect differences in the G protein-enriched cells versus wild-type cells. In contras...
Neurotransmitters and Their Receptors – 2003
EJIFCC, 2004
Much has recently been discovered and achieved in the research of neurotransmitters, and much has already been incorporated and elaborated in textbooks and handbooks. Of course, any review of these plentiful new concepts would be more or less subjective unless a longer time is allowed to elapse in-between. Like all other scientific fields, the research of neurotransmitters is characterized by the exponential growth of novel concepts. In contrast, due to the time-consuming nature of drug trials, which is dictated by the ever rising professional demands and safety requirements to be met by new drugs, this inapparent segment of these studies advances at a much slower pace, thus practicing physicians may frequently perceive the amount of novelties in the field to be rather modest. However, the possibility for novel achievements to be utilized in laboratory diagnosis lies somewhere in-between the basic discoveries and the progress in pharmacotherapy.
Principles: Receptor theory in pharmacology
Trends in Pharmacological Sciences, 2004
Pharmacological receptor theory is discussed with special reference to advances made during the past 25 years. Thus, the operational model has supplanted analysis of drug -receptor interaction in functional systems whereas the extended ternary complex model is used routinely to simulate quantitatively G-protein-coupled receptor (GPCR) behavior. Six new behaviors for GPCRs, centered on spontaneous production of receptor active states, ligand-selective receptor active states, oligomerization with other proteins (receptor and nonreceptor) and allosteric mechanisms, have been characterized and each holds the potential for new drug discovery for therapeutic benefit.
European Journal of Biochemistry, 1980
1. The affinity alkylation reaction of the cholinergic, depolarising ligand, bromoacetylcholine with reduced acetylcholine receptor in the membrane fragments of Torpedo marmorata and in Triton-solubilised receptor from cat denervated muscle has been studied. 2. Brief pretreatment with 100 pM bromoacetylcholine abolishes all [3H]a-neurotoxin binding in both cases. 3. In the receptor from each of these sources, the number of sites of specific a-neurotoxin binding is exactly equal to the number of sites that can be specifically alkylated by br~mol[~H]acetylcholine, at saturation of either ligand. 4. The concentration-dependence of specific br~mo[~H]acetylcholine binding is found to be biphasic. A first phase can be clearly discerned in which one-half of the total specific ligand-binding sites are alkylated readily, and a second phase in which the remainder react at higher reagent concentrations. The same discrimination of two equal sets of ligand sites can be obtained by preblockade using low concentrations of unlabelled bromoacetylcholine followed by reaction with [3H]a-neurotoxin or bromo[3H]acetylcholine. 5. In both phases, a single subunit of M , about 43000 is the sole site of specific alkylation in both Torpedo and muscle. The reasons for the appearance of two equal but distinct populations in the ligand binding sites in the receptors are discussed.
Ligand Binding, Activation, and Agonist Trafficking
The Adrenergic Receptors, 2006
Our understanding of adrenergic function has advanced considerably in the 15 years since three adrenergic receptor books were published in The Receptors series. In the late 1980s, many of the adrenergic subtypes had not yet been cloned. Most of the studies during that time focused on traditional pharmacological approaches in selected tissues and cell lines. We learned about structure-function relationships through the manipulation of the drug, not the receptor. We understood that there were multiple subtypes within each class of adrenergic receptors, but the functions of the subtypes were unclear because they seemed to control the same signal transduction and biological processes. Molecular cloning of the receptors led to the realization that there were many different subtypes, some not previously described by the tissue pharmacology. With the genes of these receptors in hand, the field has now advanced with more precise experiments and questions, but it has still suffered from the lack of highly selective ligands and antibodies. Foreseeing that these limitations would not be overcome any time in the near future, scientists in the adrenergic receptor field-using modern genetic approaches-started to redirect their work to answer questions about structure and function and the possible physiological and pathophysiological pathways that would be regulated by adrenergic receptors. The Adrenergic Receptors: In the 21st Century focuses on these modern approaches and was written by the scientists who developed them to elucidate adrenergic receptor function.