The Adrenergic Receptors in the 21st Century
Dianne M. Perez, PhD, ed
404 pages. Totowa, NJ: Humana Press; 2005. $165.00. ISBN 1-58829-423-4.
“What we are allowed to see of a molecule’s properties is totally dependent on the techniques of bioassay we use.”
— Sir James W. Black, Nobel Lecture, 1988
The search for the fundamental principle that governs the evolutionarily conserved “fight or flight” response to stress or exercise has fascinated biomedical researchers for more than a century, led to the discovery of neurohormones, norepinephrine, epinephrine, and adrenergic receptors (ARs), and opened the field of G protein–coupled receptor (GPCR) biology. Stimulation of ARs by these catecholamines regulates diverse physiological processes in response to a fight or flight situation, including heart beat rate and contraction strength, vascular and bronchial smooth muscle tone, energy metabolism, and central neuronal activities. During the 20th century, extraordinary progress was made in our understating of ARs. The first half of the 20th century was marked by the development of the concept of a receptor, the isolation of the first hormone (epinephrine), and the discovery of the first second messenger (cAMP). The last half of the century was signified by radioligand binding, receptor pharmacology, cloning, and genetic engineering and the resultant discovery of many subtypes of ARs and their diverse functions and signaling pathways. The most important lesson learned from the history of AR biology over the past century is that major breakthroughs depend on the innovation of powerful techniques.
With the long history and vigorous new developments of AR biology and medicine, it is essential for newcomers to glean a historical perspective and an updated comprehensive picture of the field without having to read the overwhelming literature. The Adrenergic Receptor in the 21st Century, edited by Dianne M. Perez, a renowned leader in the field of AR biology, is an excellent source of both information and inspiration. For experienced scientists or physician-scientists in the field, it is an authoritative desk book that integrates information on all AR subtypes and their pathogenic and therapeutic implications. The book consists of 15 chapters written by experts in the field, with highlights on detailed structure-function studies of ARs, information gleaned from genetically altered mouse models, and effects of AR polymorphisms on receptor signaling and clinical outcomes. In particular, Chapter 1 provides “historical perspectives from the 20th century” that guide the reader through the development and the major landmarks of the field of GPCR. Chapters 3 and 10 summarize recent progress in AR signaling, which is marked by discoveries on subtype-specific and context-dependent signaling mechanisms, homo- or heterodimerization of ARs, intermolecular interactions between ARs and scaffold/signaling proteins, and G protein–independent novel signaling pathways.
These new signaling paradigms reshape our perception of GPCR signal transduction from the traditional linear signaling cascade of ligand–receptor–G protein–second messenger–effector to a more complex, multidimensional, and integrated signalome in which an individual AR can initiate multiple signaling pathways in a temporally and spatially regulated manner.
What is truly remarkable about this field is the rapid translation of bench to bedside in addition to the rapid development of paradigms as knowledge has been assimilated. Chapter 5 is focused on the clinical applications of AR agonists, as well as antagonists in cardiovascular and pulmonary medicine and urogenital disease. Of most importance, β-AR antagonists, particularly those selective for β1-AR, have been very useful for treatment of coronary heart disease, hypertension, certain arrhythmias, and congestive heart failure. Over the recent several years, the discovery of a specific role of α1A-AR in human prostate has led to the development of α1A-AR selective antagonists as the major treatment of the highly prevalent benign prostate hyperplasia. Chapter 13 provides a whole spectrum of identification and characterization of AR polymorphisms from genetic and molecular analysis to clinical phenotypes in terms of disease susceptibility, prognosis, and response to AR agonists or antagonists. The knowledge of AR polymorphisms has deepened our understanding of clinical phenotype–genotype relations and has also provided the rationale for genetic diagnosis, personalized therapeutics, and potential gene therapy approaches for various disorders such as asthma, congestive heart failure, and hypertension.
In Chapters 8 to 11, the readers are enchanted by recent studies using genetically engineered mice for all 9 AR subtypes. These studies have shed new light on our understanding of the physiological and pathophysiological significances of each AR subtype in the whole body in general and in cardiovascular system in particular. Cutting-edge techniques for spatial, temporal, and genome-wide analysis of ARs, such as fluorescent labeling and cDNA microarray, are reviewed in Chapters 6, 7, and 14.
Despite the fact that we have already learned so much about this amazing receptor system, many fundamental principals controlling the temporal and spatial AR signaling characteristics and their disease-related regulation remain elusive. We shall enthusiastically look forward to a more comprehensive picture of ARs in the 21st century, as new techniques such as functional genomical and proteomical bioassays are more matured and innovatively adopted to the field of AR biology.
Overall, this book is well written for a general audience and puts the scientific advances into a historical and philosophical context while keeping the technicalities under control. The authors make serious attempts to bring the reader to the very frontier of the field. The book not only provides updated, detailed information on ARs but also challenges us to develop innovative techniques and deepen our understanding of the fundamental principles dictating the temporal and spatial signaling properties of ARs, which may lead to more specific, effective, and personalized novel therapeutics. Thus, I would enthusiastically recommend this book to clinicians, bench scientists, and students, as well as a general audience who wish to gain a global appreciation of the field of AR research in the past and present centuries.