ABSTRACT
There is a large body of experimental evidence that is compatible with the presence of heterodimers of the major A subclass of G protein-coupled receptors (GPCRs) and suggests that these heterodimers might have different functional properties from those of the monomers (or homodimers) of the individual receptors that engage in heterodimer formation. The question is whether there are allosteric interactions across the receptor-receptor interface of a heterodimer that modulate the binding properties of the heterodimer components and thereby change their pharmacology. In this review, I examine published experimental evidence from radioligand binding studies in the context of different models of allosterism and discuss a number of apparently discrepant results. The analysis suggests that more experimental data are required if equal, two-way, crossreceptor interactions within a GPCR heterodimer, at the level of binding, are to be unequivocally demonstrated.
Subject(s)
GTP-Binding Proteins/metabolism , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Allosteric Site , Animals , Binding Sites , Humans , Protein Multimerization , Radioligand Assay , Receptor, Cannabinoid, CB1/chemistry , Receptor, Cannabinoid, CB1/metabolism , Receptors, Catecholamine/chemistry , Receptors, Catecholamine/metabolism , Receptors, Chemokine/chemistry , Receptors, Chemokine/metabolism , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/metabolism , Receptors, Neuropeptide/chemistry , Receptors, Neuropeptide/metabolismABSTRACT
A new detection scheme for catecholamines was constructed through embedding synthetic receptors within vesicles comprising phospholipids and polydiacetylene. Fluorescence emission of the polydiacetylene was induced through specific interactions between the soluble ligands and the vesicle-incorporated hosts. The system demonstrated remarkable selectivity among structurally similar ligands and achieved much lower detection thresholds compared to that of other reported catecholamine sensors. The chromatic assembly provides a generic route for high sensitivity detection of ligand-receptor interactions.
Subject(s)
Acetylene/analogs & derivatives , Catecholamines/analysis , Micelles , Polymers/chemistry , Receptors, Catecholamine/chemistry , Surface-Active Agents/chemistry , Acetylene/chemistry , Catecholamines/chemistry , Colorimetry , Fluorescence , Polyacetylene Polymer , PolyynesABSTRACT
Catecholamines (CAs) realise activity of certain cerebral neurons, sympathoadrenal system and peripheral cells producing dopamine. CAs control metabolism, template biosynthesis, cytological, physiological and psychological processes. During recent 10-15 years complex employment of various interdisciplinary approaches (including molecular biology techniques) resulted in some important achievements. Cellular transporters and 10 individual receptors were discovered and studied. Basic mechanisms of CA signal transduction into nucleus and mitochondria, regulation of gene expression, hyperplasia, hypertrophy and biological oxidation have been recognised. It was found that besides central neurotransmitter action DA also acts as peripheral auto- and paracrinic hormone. CA participate in pathogenesis of many illnesses and in the defence mechanisms of a body. CA and related substances are effective and widely used drugs.
Subject(s)
Catecholamines/physiology , Animals , Brain/metabolism , Brain/physiology , Catecholamines/metabolism , Catecholamines/therapeutic use , Cell Membrane/metabolism , Cell Nucleus/metabolism , Disease , Dopamine/metabolism , Dopamine/physiology , Epinephrine/metabolism , Epinephrine/physiology , Humans , Norepinephrine/metabolism , Norepinephrine/physiology , Receptors, Catecholamine/chemistry , Receptors, Catecholamine/drug effects , Receptors, Catecholamine/physiology , Signal Transduction/physiology , Sympathetic Nervous System/metabolism , Sympathetic Nervous System/physiologyABSTRACT
One of the key events in the actions of agonists and antagonists is their binding to receptors. Understanding this event is of interest in terms of understanding receptor function but it also has immense practical relevance for the design of drugs. If the ligand-binding process could be understood in detail, including the nature of the interactions made between ligand and receptor, then this could help in the design of more-selective drugs. The interaction of a ligand with its receptor is clearly of importance in determining the specificity of ligand action but ligand-receptor interaction also initiates the processes of signalling that are exhibited in the efficacy of ligand action. Here Philip Strange considers these events for catecholamine receptors, concentrating mostly on dopamine receptors; where necessary the discussion is widened to include other receptor systems.
Subject(s)
Receptors, Catecholamine/metabolism , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Drug Design , Hydrogen Bonding , Ligands , Mutation/genetics , Receptors, Catecholamine/chemistry , Receptors, Catecholamine/genetics , Receptors, Dopamine D1/chemistry , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/chemistry , Receptors, Dopamine D2/geneticsABSTRACT
A genomic DNA fragment encoding a G protein-coupled seven-transmembrane receptor was isolated from Medaka fish, Oryzias latipes. The encoded protein is similar in sequence to other receptors including catecholamine, histamine and serotonin receptors. However, the similarity is much lower than those among members of these receptor subfamilies, thus suggesting this seven-transmembrane receptor to be an orphan receptor whose ligand has not yet been identified. Genomic Southern blot analysis suggested that the fish genome contains additional receptor genes related to the isolated gene, indicating that this novel receptor, possibly with its related receptors, might constitute a novel subfamily of the seven-transmembrane receptor superfamily.
