Receptors – serie

During the past decade, great strides have been made in our un­ derstanding of the biochemistry and pharmacology of the alpha-l adrenergic receptor.

Serotonin (5-HT) was isolated and chemically characterized nearly four decades ago, and is now generally accepted to function as a neurotransmitter and neuromodulatory agent. Early research focused on the measurement of concentrations, synthesis, and metabolism of 5-HT, and only recently has the focus shifted to characterization of 5-HT receptors. Gaddum and Picarelli first sug­ gested in 1957 that the effect of 5-HT in the guinea pig ileum is mediated by two pharmacologically distinguishable receptors; however, the possibility of dual5-HT receptors was not explored systematically or successfully until the past decade. It is now clear that more, perhaps many more, subclasses of 5-HT receptors exist. The purpose of this book is to provide an up-to-date report on 5-HT receptors. This is a difficult task considering the astonishing speed at which research in this field is expanding. As the first of what we can expect to be a steady stream of monographs focusing on 5-HT receptors, the book confirms that we are in an exciting time in the history of 5-HT. For those of us who have been work­ ing on 5-HT for many years, our dream of equal progress and recognition with the more extensively studied catecholamines is finally being realized. We now have a Serotonin Club that held its first international scientific meeting in 1987, and several more international meetings are in the planning stages.

Research on muscarinic receptors is advancing at an extraordinary rate. Ten years ago, the existence of muscarinic receptor sub­ types was a logical assumption with only scattered experimen­ tal support. The discovery that pirenzepine recognized apparent heterogeneity in muscarinic binding sites infused new life into the problem of subclassifying muscarinic receptors. Simultaneous advances in molecular biology created a frenzy to clone cell sur­ face receptors. The muscarinic receptor succumbed surprisingly quickly, revealing its structure and that of at least four closely related gene products within a year. Our hope of obtaining clear evidence for muscarinic receptor subtypes was answered with a vengeance. Now a family of muscarinic receptors sits before us, asking to be understood. The bounty is as attractive to those who have not previously studied muscarinic receptors as to those who have dedicated their research careers to this subject. The goal of this book is to ensure that the new generation of research will profit from the wisdom of the past. The tools of molecular biology are well suited to the tasks of characteriz­ ing the pharmacology, function, and regulation of the distinct muscarinic receptor subtypes. However, efficient and intelligent use of these tools is not possible, unless one understands the properties of the receptor, the molecular mechanisms by which it couples to effectors, and the ways that it is regulated.

Historically, the major emphasis on the study of purinergic systems has been predominantly in the areas of physiology and gross pharmacology. The last decade has seen an exponential in- crease in the number of publications related to the role of both adenosine and A TP in mammalian tissue function, a level of interest that has evolved from a more molecular focus on the identity of adenosine and A TP receptor subtypes and the search for selective ligands and development of radioligand binding assays by Fred Bruns and colleagues (especially that for A receptors) that played z a highly significant role in advancing research in the area. In the 60 years since adenosine was first shown to be a potent hypotensive agent, a considerable investment has been made by several pharmaceutical companies-including Abbott, Byk Gulden, Takeda, Warner-LambertlParke Davis, Boehringer Mann- heim, Boehringer Ingelheim, Nelson/Whitby Research and CffiA- Geigy-as well as John Daly's laboratory at the National Institutes of Health, to design new adenosine receptor ligands, and both agon- ists and antagonists with the aim of developing new therapeutic entiities.Numerous research tools have derived from these efforts including: 2-chloroadenosine, R-PIA (~-phenylisopropyladeno- sine; NECA (5' N-ethylcarboxamidoadenosine); CV1808; CI936; PD 125,944; ~-benzyladenosine; PACPX; CPX; CPT; XAC; CGS 15943 and CGS 21680. Yet in the realm of therapeutics it was only in 1989 that adenosine itself was approved for human use in the treatment of supraventricular arrythmias.

Prior to 1974, the ~adrenergic receptors were known only in- directly as entities that responded to drugs in a selective manner to mediate a variety of physiologically important responses. During the intervening years, our view of ~adrenergic receptors has changed dramatically. The availability of high affinity 125I-labeled radioligands selective for these receptors presaged an explosion of experimenta- tion utilizing direct binding assays to establish the biochemical properties of the receptor protein. In the opening chapter, Stadel and Lefkowitz describe this development and its impact on our under- standing of the molecular basis of ~adrenergic receptor function. The availability of well-characterized receptor ligands, coupled with the development of efficient methods for detergent solubilization, formed the basis of receptor purification using affinity chromatography. The related technique of photoaffinity labeling provided a means to estimate the molecular mass of these receptors. The availability of substantial amounts of purified ~2-adrenergic receptor allowed determination of segments of its amino acid se- quence.This information led to the production of polynucleotide probes and eventually to cloning of the receptor gene and determi- nation of the complete primary sequence of the receptor protein. Caron and Lefkowitz review the investigations leading to this major development and discuss the methods involved. They analyze our current perception of the relation of receptor function to its structure and discuss the general features of the G protein-interacting receptor family, of which the ~-adrenergic receptors are prototypes.

Offers a state-of-the-art review by international experts on all aspects of tachykinin receptors, including neuropeptide/peptide and G-protein-linked receptors in general. It covers the physiology, pharmacology, biochemistry, and molecular biology of these receptors from both clinical and basic research points of view. Topics treated by the distinguished contributors include the characterization of tachykinin receptors, the mechanisms of tachykinin receptor action, a reflection on future prospects, and a historical consideration of tachykinin research.

It is the goal of The Metabotropic Glutamate Receptors to provide acomprehensive and forward-thinking review ofthe tremen- dous advances that have occurred in less than a decade of metabotropic glutamate receptors (mGluR) research. Virtually every areaof mGluR research is covered, including the molecular biology, pharmacology, anatomical distribution, and physiological and pathological roles of mGluRs. It is our intention that this volume not only summarize what is now known about the mGluRs, but also illuminate the areas in which there is the greatest need for focused research. Glutamic acid is an amino acid that has long been known to play several important metabolic roles in central and peripheral tissues and to be a component of several naturally occurring molecules. The first evidence that glutamate mayaIso serve as a neurotransmitter in the central nervous system (CNS) came in the late 1950s and early 1960s when glutamate and other acidic amino acids were found to induce behavioral convulsions when topically applied to the cortex and to excite a wide variety of central neurons.These findings spurred a massive research effort that quickly established glutamate as the pri- mary excitatory neurotransmitter in the vertebrate CNS. One of the most striking characteristics of glutamate that was quickly recognized was its ubiquitous role in serving as the neurotransmitter at the vast majority of excitatory synapses in the brain. It is now clear that most central neuronal circuits involve glutamatergic neurotransmission at some level.

A state-of-the-art summary from leading laboratories around the world of our current knowledge of the molecular biology, the physiology, and the pharmacology of the P2 receptors. The authoritative contributions cover the major aspects of these receptors, describing the relationships between physiological and pharmacological effects of ATP and other nucleotides and the various cloned P2 receptors, as well as providing an historical perspective and discussing current issues of nomenclature. They also illuminate how P2 receptor structures contribute to their function, including the physical differences underlying the pharmacological and functional variations among P2 receptor subtypes.

The field of the excitatory amino acids was born when L-glutamate and L-aspartate were found to be potent convulsants (Hayashi, 1954), and were subsequently found to excite neurons directly (Curtis, Phillis, and Watkins, 1959). Although these studies initiated the hypothesis of glutamate-mediated neurotransmission, it was noted that the ubiquitous actions of glutamate could also reflect a general, nonspecific property of glutamate on neuronal mem- branes. It was not until 20 years later that pharmacological, physiological, and biochemical studies provided convincing evidence for a neurotransmitter role for glutamate in the mammalian central nervous system (CNS). With the critical demonstration that the pharmacologically defined glutamate receptors mediate synaptic currents, glutamate rapidly became widely accepted as a majorneurotransmitter by the mid-1980s. This breakthrough, together with the simultaneous findings that glutamate receptors are involved in many essential, as well as pathological, processes in the CNS, instantly transformed the study of glutamate receptors into one of the fastest-growing and most exciting areas of neuroscience.With the cloning of numerous ionotropic glutamate receptor subunits over the last six years, the field has experienced another dramatic acceleration in the understanding of receptor action and in providing the first clear insights into the molecular bases underlying the wealth of pharmacological and physiological data on these receptors.

Roger Cone and a distinguished team of expert investigators provide the first major treatment of this critically important receptor family. The book illuminates the structure and function of these receptors through a wide-ranging review of the latest findings concerning the biology, physiology, and pharmacology of their peptide ligands and covers the major melanocortin peptides, Melanocortin-1-Receptors through Melanocortin-5-Receptors. Topics include the characterization of the melanocortin receptors, the biochemical mechanism of receptor action, and receptor function and regulation. Timely and authoritative, The Melanocortin Receptors offers an up-to-date knowledge base on the remarkably complex structure and functions of the melanocortins, a guide that will prove invaluable for today's neuroscientists, endocrinologists, pharmacologists, and other clinical and experimental investigators working in this fast moving field.

Offers a state-of-the-art review by international experts on all aspects of tachykinin receptors, including neuropeptide/peptide and G-protein-linked receptors in general. It covers the physiology, pharmacology, biochemistry, and molecular biology of these receptors from both clinical and basic research points of view.Topics treated by the distinguished contributors include the characterization of tachykinin receptors, the mechanisms of tachykinin receptor action, a reflection on future prospects, and a historical consideration of tachykinin research.

Prior to 1974, the ~adrenergic receptors were known only in- directly as entities that responded to drugs in a selective manner to mediate a variety of physiologically important responses. During the intervening years, our view of ~adrenergic receptors has changed dramatically. The availability of high affinity 125I-labeled radioligands selective for these receptors presaged an explosion of experimenta- tion utilizing direct binding assays to establish the biochemical properties of the receptor protein. In the opening chapter, Stadel and Lefkowitz describe this development and its impact on our under- standing of the molecular basis of ~adrenergic receptor function. The availability of well-characterized receptor ligands, coupled with the development of efficient methods for detergent solubilization, formed the basis of receptor purification using affinity chromatography. The related technique of photoaffinity labeling provided a means to estimate the molecular mass of these receptors. The availability of substantial amounts of purified ~2-adrenergic receptor allowed determination of segments of its amino acid se- quence.This information led to the production of polynucleotide probes and eventually to cloning of the receptor gene and determi- nation of the complete primary sequence of the receptor protein. Caron and Lefkowitz review the investigations leading to this major development and discuss the methods involved. They analyze our current perception of the relation of receptor function to its structure and discuss the general features of the G protein-interacting receptor family, of which the ~-adrenergic receptors are prototypes.

A state-of-the-art summary from leading laboratories around the world of our current knowledge of the molecular biology, the physiology, and the pharmacology of the P2 receptors. The authoritative contributions cover the major aspects of these receptors, describing the relationships between physiological and pharmacological effects of ATP and other nucleotides and the various cloned P2 receptors, as well as providing an historical perspective and discussing current issues of nomenclature. They also illuminate how P2 receptor structures contribute to their function, including the physical differences underlying the pharmacological and functional variations among P2 receptor subtypes.

The field of the excitatory amino acids was born when L-glutamate and L-aspartate were found to be potent convulsants (Hayashi, 1954), and were subsequently found to excite neurons directly (Curtis, Phillis, and Watkins, 1959). Although these studies initiated the hypothesis of glutamate-mediated neurotransmission, it was noted that the ubiquitous actions of glutamate could also reflect a general, nonspecific property of glutamate on neuronal mem- branes. It was not until 20 years later that pharmacological, physiological, and biochemical studies provided convincing evidence for a neurotransmitter role for glutamate in the mammalian central nervous system (CNS). With the critical demonstration that the pharmacologically defined glutamate receptors mediate synaptic currents, glutamate rapidly became widely accepted as a majorneurotransmitter by the mid-1980s. This breakthrough, together with the simultaneous findings that glutamate receptors are involved in many essential, as well as pathological, processes in the CNS, instantly transformed the study of glutamate receptors into one of the fastest-growing and most exciting areas of neuroscience.With the cloning of numerous ionotropic glutamate receptor subunits over the last six years, the field has experienced another dramatic acceleration in the understanding of receptor action and in providing the first clear insights into the molecular bases underlying the wealth of pharmacological and physiological data on these receptors.

Research on muscarinic receptors is advancing at an extraordinary rate. Ten years ago, the existence of muscarinic receptor sub­ types was a logical assumption with only scattered experimen­ tal support. The discovery that pirenzepine recognized apparent heterogeneity in muscarinic binding sites infused new life into the problem of subclassifying muscarinic receptors. Simultaneous advances in molecular biology created a frenzy to clone cell sur­ face receptors. The muscarinic receptor succumbed surprisingly quickly, revealing its structure and that of at least four closely related gene products within a year. Our hope of obtaining clear evidence for muscarinic receptor subtypes was answered with a vengeance. Now a family of muscarinic receptors sits before us, asking to be understood. The bounty is as attractive to those who have not previously studied muscarinic receptors as to those who have dedicated their research careers to this subject. The goal of this book is to ensure that the new generation of research will profit from the wisdom of the past. The tools of molecular biology are well suited to the tasks of characteriz­ ing the pharmacology, function, and regulation of the distinct muscarinic receptor subtypes. However, efficient and intelligent use of these tools is not possible, unless one understands the properties of the receptor, the molecular mechanisms by which it couples to effectors, and the ways that it is regulated.

Historically, the major emphasis on the study of purinergic systems has been predominantly in the areas of physiology and gross pharmacology. The last decade has seen an exponential in- crease in the number of publications related to the role of both adenosine and A TP in mammalian tissue function, a level of interest that has evolved from a more molecular focus on the identity of adenosine and A TP receptor subtypes and the search for selective ligands and development of radioligand binding assays by Fred Bruns and colleagues (especially that for A receptors) that played z a highly significant role in advancing research in the area. In the 60 years since adenosine was first shown to be a potent hypotensive agent, a considerable investment has been made by several pharmaceutical companies-including Abbott, Byk Gulden, Takeda, Warner-LambertlParke Davis, Boehringer Mann- heim, Boehringer Ingelheim, Nelson/Whitby Research and CffiA- Geigy-as well as John Daly's laboratory at the National Institutes of Health, to design new adenosine receptor ligands, and both agon- ists and antagonists with the aim of developing new therapeutic entiities.Numerous research tools have derived from these efforts including: 2-chloroadenosine, R-PIA (~-phenylisopropyladeno- sine; NECA (5' N-ethylcarboxamidoadenosine); CV1808; CI936; PD 125,944; ~-benzyladenosine; PACPX; CPX; CPT; XAC; CGS 15943 and CGS 21680. Yet in the realm of therapeutics it was only in 1989 that adenosine itself was approved for human use in the treatment of supraventricular arrythmias.

Serotonin (5-HT) was isolated and chemically characterized nearly four decades ago, and is now generally accepted to function as a neurotransmitter and neuromodulatory agent. Early research focused on the measurement of concentrations, synthesis, and metabolism of 5-HT, and only recently has the focus shifted to characterization of 5-HT receptors. Gaddum and Picarelli first sug­ gested in 1957 that the effect of 5-HT in the guinea pig ileum is mediated by two pharmacologically distinguishable receptors; however, the possibility of dual5-HT receptors was not explored systematically or successfully until the past decade. It is now clear that more, perhaps many more, subclasses of 5-HT receptors exist. The purpose of this book is to provide an up-to-date report on 5-HT receptors. This is a difficult task considering the astonishing speed at which research in this field is expanding. As the first of what we can expect to be a steady stream of monographs focusing on 5-HT receptors, the book confirms that we are in an exciting time in the history of 5-HT. For those of us who have been work­ ing on 5-HT for many years, our dream of equal progress and recognition with the more extensively studied catecholamines is finally being realized. We now have a Serotonin Club that held its first international scientific meeting in 1987, and several more international meetings are in the planning stages.

During the past decade, great strides have been made in our un­ derstanding of the biochemistry and pharmacology of the alpha-l adrenergic receptor. The alpha-l adrenergic receptor plays a key role in biological function. This is evidenced by the fact that the alpha-l adrenergic receptor plays a prominent functional role in most organs of the body and in the key systems responsible for survival of the organism and maintenance of optimum biological activity. This is most apparent in the cardiovascular system, in which alpha-l adrenergic receptors are the single most important receptor involved in the maintenance of blood pressure and circu­ latory function. It is appropriate, therefore, that recent findings related to the pharmacology and biochemistry of the alpha-l adrenergic receptor be compiled, since this subject has not been reviewed in detail in recent years. It is the purpose of this book to present a series of reviews of key experimental findings that shed new light on the alpha-l adrenergic receptor and the manner in which it functions. Classically, most receptors have been characterized based on structure-activity relationships obtained for selective agonists and antagonists interacting with the receptor. Although there are many newer and more sophisticated approaches to receptor char­ acterization, structure-activity relationships still provide impor­ tant information regarding the chemical requirements made by the receptor for its occupation by ligands and its subsequent acti­ vation by those ligands possessing intrinsic efficacy and, there­ fore, agonist activity.

This book is intended as a scientific resource for cannabinoid researchers carrying out animal and human experiments, and for those who are interested in learning about future directions in cannabinoid research. Additionally, this book may be of value to investigators currently working outside the field of cannabinoid research who have an interest in learning about these compounds and their atypical cannabinoid signalling. This book provides insight into the potential medical application of cannabinoids and their therapeutic development for the treatment of human disease.

The following remarks are intended to serve as an introduction to this particular volume as well as to the whole series of volumes of which this is the first. The intent of the series is to provide an authentic and relatively complete statement about the status of our understanding of the receptors. The models we had in mind while developing this series are The Enzymes, The Proteins, and comparable groups of books. The receptors have received a degree of importance and richness of understanding that makes them deserving of comprehensive and complete coverage. The study of these molecules, which may well include such diverse items as the receptors for hormones, neurohumors, pheromones, taste, and many other chemical signals, have a great deal in common, so that the student of any one of them will wish to know the status of research about the others. This com­ monality is in part substantive, and in part practical and procedural. Substantively, the receptors are all macromolecules whose function is to re­ ceive some form of chemical signal and transduce it to a form which is usable by the receiving cell. In this way, a chemical signal may lead to a neural response, to the turning-on of a cell's chromosomes, or to the activation of some enzymic apparatus to produce or release a substance. Because most of these processes are noncatalytic, special techniques not previously commonplace in biochemistry have been developed in order to study the receptors.

This book is intended as a scientific resource for cannabinoid researchers carrying out animal and human experiments, and for those who are interested in learning about future directions in cannabinoid research. Additionally, this book may be of value to investigators currently working outside the field of cannabinoid research who have an interest in learning about these compounds and their atypical cannabinoid signalling. This book provides insight into the potential medical application of cannabinoids and their therapeutic development for the treatment of human disease.

The Ghrelin receptor was identified before its natural ligand ghrelin. This receptor is found both centrally and peripherally, and has been shown to affect various processes, such as food intake, gut motility, memory, glucose and lipid metabolism, cardiovascular performances, reproduction, memory, and immunological responses, amongst others. The functions of the ghrelin receptor in the central nervous system are numerous and are still being explored. In this book we specifically focus on the various roles of the ghrelin receptor in the central nervous system. In a first set of chapters, the book will focus on the discovery and the properties of this intriguing constitutively active G-protein coupled receptor, on its multiple intracellular transduction mechanisms and the various subtypes of the currently known ghrelin receptor complexes. Next, the book will elaborate on the mitochondrial mechanisms regulated by the ghrelin receptor, its role in feeding and drug addictive mechanisms, memory, sleep and arousal. The final chapters focus on the potential of this receptor as a target for the treatment of neurological disorders including Parkinson’s disease, epilepsy, anxiety and depression.

A comprehensive overview of nicotinic receptors that addresses their history from crystal structure to behavior as well as their implications in disease and potential as therapeutic targets. It includes background information on all subtypes of nicotinic receptors, the most recent information on the distribution throughout the nervous system and discussion of their implications in learning and memory, addiction and neurological and psychiatric disease such as Alzheimer's and Parkinson's. Takes advantage of several recent developments in the fields of optogenetics, viral expression and gene analysis to focus on current knowledge on the functional aspects of nicotinic receptors.

GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABAA and GABAB receptors. Recently, a novel form of GABAA receptor-mediated inhibition, termed “tonic” inhibition, has been described. Whereas synaptic GABAA receptors underlie classical “phasic” GABAA receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABAA receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABAA receptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This book highlights ongoing work examining the properties of recombinant and native extrasynaptic GABAA receptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABAA receptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.

The Ghrelin receptor was identified before its natural ligand ghrelin. This receptor is found both centrally and peripherally, and has been shown to affect various processes, such as food intake, gut motility, memory, glucose and lipid metabolism, cardiovascular performances, reproduction, memory, and immunological responses, amongst others. The functions of the ghrelin receptor in the central nervous system are numerous and are still being explored. In this book we specifically focus on the various roles of the ghrelin receptor in the central nervous system. In a first set of chapters, the book will focus on the discovery and the properties of this intriguing constitutively active G-protein coupled receptor, on its multiple intracellular transduction mechanisms and the various subtypes of the currently known ghrelin receptor complexes. Next, the book will elaborate on the mitochondrial mechanisms regulated by the ghrelin receptor, its role in feeding and drug addictive mechanisms, memory, sleep and arousal. The final chapters focus on the potential of this receptor as a target for the treatment of neurological disorders including Parkinson’s disease, epilepsy, anxiety and depression.

Functional selectivity refers to the ability of different ligands acting at one receptor subtype to activate multiple signaling pathways in unique combinations; that is, one drug can be an agonist at pathway A and an antagonist or partial agonist at pathway B, and another drug can have the reverse profile. Functional selectivity has profound implications for drug development, for chemical biology, and for the design of experiments to characterize receptor function. In Functional Selectivity of G Protein-Coupled Receptors expert neuroscientists and pharmacologists review the work that demonstrated the existence of functional selectivity, placed it within a theoretical framework, and provided a mechanistic basis for the phenomenon. This exciting, comprehensive, and future-oriented volume includes chapters that focus on theoretical and mechanistic aspects of functional selectivity and that cut across subfamilies of GPCRs. Additional chapters focus on subfamilies of therapeutically relevant receptors where there is considerable evidence of ligand functional selectivity. Accessible and authoritative, Functional Selectivity of G Protein-Coupled Receptors is a valuable educational tool and reference source for students and scientists interested in drug development, chemical biology, and GPCR function.