► G-protein-coupled receptors (GPCRs) are the largest family of receptors in the human genome, are ubiquitously expressed on the surface of all cells, and constitute the predominant signaling system in living organisms. Given that hormone and neurotransmitter activity at GPCRs is such a prevalent phenomenon in virtually every physiological process, it is not surprising that aberrations in GPCR-mediated signal transduction have been associated with many disease states, including CNS disorders, metabolic disorders, cardiovascular disease, and many cancers. Approximately 30% of all medicines currently on the market target GPCRs, but this figure only relates to a small fraction of the total number of GPCRs that could be effectively exploited therapeutically. Thus, these receptors remain one of the most tractable and widely pursued groups of drug targets.
Structurally, GPCRs are defined by a common architecture composed of an extracellular N-terminal domain, an intracellular C-terminal domain, and seven transmembrane domains linked by three extracellular and three intracellular loops (Fig. 1). Despite this common architecture, GPCRs exhibit a remarkable diversity in the range of ligands that they recognize and the intracellular signal transduction cascades that they couple to, which is indicative of a very flexible and dynamic nature. Mammalian GPCRs are further subdivided into three groups: Family A or Class I GPCRs (''rhodopsin-like''), the largest family comprising receptors for prototypical neurotransmitters and hormones such as biogenic amines (epinephrine, norepinephrine, ► serotonin, ► dopamine, histamine, acetylcholine), adenosine, ► cannabinoids and angiotensin; Family B or Class II GPCRs, incorporating peptide hormone receptors such as calcitonin, parathyroid hormone, glucagon, and secretin receptors; and Family C or Class III GPCRs, including receptors for small molecules such as ► glutamate, ► GABA, and calcium (Fig. 1).
For many years, the traditional view of signaling via GPCRs posited that these receptors were quiescent in the absence of ligand, and that activation was mediated by a ligand-induced conformational change that subsequently promoted coupling to a variety of members of the hetero-trimeric G-protein family to initiate intracellular signal transduction. This simplistic view was considered consistent with the (even older) phenomenological classification of drugs as either ► agonist or ► antagonist, i.e., compounds that activated the system were agonists, whereas compounds that had no apparent effect on the system but could block the actions of agonists were classed as antagonists. However, it is now known that GPCR-mediated signaling is a more complex process than originally envisaged, and a number of important developments in the field have led to a reclassification of the molecular nature of drugs and a change in the approaches used to screen for them. One of these developments was the discovery that GPCRs, like many other proteins, can spontaneously adopt one or more active states in the absence of ligand. This ligand-independent activity is termed ► constitutive activity and is now acknowledged as a naturally occurring phenomenon for nearly all GPCRs to varying extents. A second, more recent, development is the recognition that different active states of a GPCR can be coupled to markedly different signal transduction processes, some of them in a G-protein-independent manner, and that not all states are promoted by all ligands that recognize the GPCR. This dynamic, ''multi-conformational,'' view of GPCR activity has led to a re-evaluation of the molecular nature of drug efficacy and highlighted the inadequacy of the simple agonist/antagonist paradigm for describing the effects of drugs. In particular, it is now evident that the role of a ligand is to stabilize one or more GPCR states for which it has the highest affinity and, by doing so, bias the possible conformations of the receptor toward those states. In this new paradigm, agonists are ligands that promote GPCR active states over and above those states that occur spontaneously, whereas ligands that promote inactive states, i.e., reduce the constitutive (basal) activity of a signaling pathway, are termed inverse agonists (Fig. 2). Compounds that bind to the GPCR but do not bias the distribution of active to inactive states are termed ► neutral antagonists.
Inverse Agonists. Fig. 1. The three major families of mammalian G-protein-coupled receptors (GPCRs) with some representative examples of their endogenous agonists.
This chapter briefly considers the implications of these ligand behaviors for drug action and therapeutics.
Was this article helpful?