The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the β₂-adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts.

G-protein-coupled receptor (GPCR)-mediated signal transduction is central to human physiology and disease intervention, yet the molecular mechanisms responsible for ligand-dependent signalling responses remain poorly understood. In class A GPCRs, receptor activation and G-protein coupling entail outward movements of transmembrane helix 6 (TM6). Here, using single-molecule fluorescence resonance energy transfer imaging, we examine TM6 movements in the β₂ adrenergic receptor (β₂AR) upon exposure to orthosteric ligands with different efficacies, in the absence and presence of the G_s heterotrimer. We show that partial and full agonists differentially affect TM6 motions to regulate the rate at which GDP-bound β₂AR–G_s complexes are formed and the efficiency of nucleotide exchange leading to G_s activation. These data also reveal transient nucleotide-bound β₂AR–G_s species that are distinct from known structures, and provide single-molecule perspectives on the allosteric link between ligand- and nucleotide-binding pockets that shed new light on the G-protein activation mechanism.

<!--#include virtual="/journals/includes/copyright/hrq2002_bnr.htinc"--> Human Rights Quarterly 24.3 (2002) 573-639 In the last decade, there has been a burgeoning interest in the question of how countries recover from episodes of mass violence or gross human rights violations. ² This interest has focused on the concept of transitional justice, a term we use to describe the processes by which a state seeks to redress the violations of a prior regime. ³ Despite the fact that military and political leaders who ordered or directed mass terror generally have evaded accountability for their deeds, justice—in the form of criminal trials—has [End Page 574] been the rallying cry of many who seek to repair the injury individuals and communities have sustained as a result of these heinous acts. ⁴ As dictatorships and repressive regimes fell in Latin America in the 1980s and 1990s, human rights scholars and advocates pressed states to initiate domestic criminal proceedings against the notorious intellectual authors of mass terror and their faithful subordinates. ⁵ However, the fragile democracies, weak judiciaries, and amnesty laws made domestic trials difficult to institute. ⁶ Further, the character of war has shifted from inter- to intra-state conflict since World War II. ⁷ These wars reflect intense competition for power and [End Page 575] wealth among groups struggling for supremacy. Often characterized as racially, ethnically, or tribally motivated, one commonality among these conflicts is that warring forces target civilian populations, particularly women and children, and cause massive destruction of infrastructure. ⁸ Mass violence results in the breakdown of societal structures—social and economic institutions, and networks of familial and intimate relationships that provide the foundation for a functioning community. ⁹ Indiscriminate and episodic violence occurs at random and affects people at a neighborhood level. Even where the violence is centrally planned (as in Bosnia-Herzegovina or Rwanda), ¹⁰ the collaboration of paramilitary with military units produces acts of violence and cruelty that are designed not only to kill but to terrorize and destroy the basis of community life. ¹¹ Neighbor-on-neighbor violence is [End Page 576] characteristic of this form of aggression as seemingly peaceful community members are swept up in the inexorable process of killing. ¹² Thus, human suffering at a communal level is a shared feature of contemporary conflict. Yet, with the exception of the Nuremberg and Tokyo Tribunals, there have been no international mechanisms for accountability until the recent ad hoc criminal tribunals for the former Yugoslavia and Rwanda. ¹³ Drawing on the Latin American context, international criminal trials have become a significant response to mass violence, ¹⁴ and this trend is strengthened as the International Criminal Court ("ICC") comes closer to a creation. ¹⁵ [End Page 577] Thus, the predominant mechanism to respond to mass violence focuses on individual perpetrators of war crimes and other serious violations of international law. Frequently, advocates for this model suggest that international trials may be the single most appropriate response to communal violence. While transitional justice scholars recognize that judicial and truth-seeking mechanisms constitute one important component of a...