Adrenergic receptor responsiveness and congestive heart failure

Abstract

Our knowledge and understanding of the structure, mechanism of action and regulation of receptor-adenylate cyclase systems have increased dramatically in the last few years. A family of receptors (including the β-adrenergic receptors) and guanine nucleotide regulatory proteins (G proteins) have been purified and cloned. Structure-function studies are beginning to provide insight into how the various components of the transmembrane signaling apparatus interact to promote alterations in the activity of the effector systems. Much effort has been devoted to understanding how various pathophysiologic conditions, such as ischemia or congestive heart failure, and the therapeutic methods used to treat such conditions perturb or regulate receptor systems. It has become abundantly clear that such regulation does occur but is not restricted to simple alterations in receptor number, and may well involve covalent modification (phosphorylation) of receptors or alteration in the ability of receptors to interact with G proteins. In addition, regulation of the quantity or functionality of the various G proteins and the catalytic unit of adenylate cyclase itsett appear to occur. For example, recent evidence suggests that congestive heart failure in humans is associated with a decreased number of β-adrenergic receptors as well as an increased quantity of the inhibitory G protein (G i). These alterations may provide important insight into how to develop new therapeutic methods. Mechanisms generally responsible for transmembrane signaling, how the components are regulated by pathophysiologic conditions, and drugs used to treat disease states are discussed in detail.