oa Editorial [Hot Topic: From Structural Plasticity to Functional Diversity of 7TMRs: Biased Agonism and Beyond (Executive Guest Editor: Christodoulos S. Flordellis)]

The cells need to respond rapidly and with high fidelity to their changing environment, having in their disposition a low abundance of signaling components in cell membranes. To achieve this task, plasticity is needed. Growing evidence has shown that structural plasticity provides the cell with the required diversity. Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs) are the most diverse family of receptors in the human genome and the most frequent targets for prescribed therapeutics [1]. In recent years there has been a radical reconceptualization of the components and the organization of the 7TMR signaling machinery and the way they transduce signals to their effectors, with profound implications for drug design and development strategies. The original concepts of rigidity and stability have been replaced by the concept of structural plasticity of the 7TMR signaling apparatus, as the basis for understanding the 7TMR functional complexity [2]. The topics selected for the present issue illustrate the major advances and the revisions, that have been made in the biological and pharmacological conceptualization of 7TMRs, focusing in particular on biased agonism. As long as receptors were viewed as bimodal switches, which oscillate only between two alternative conformations, related to the active (R*) versus inactive (R) functional states, differences in ligand efficacy were attributed to the accumulation of the stabilized single active state [1, 3]. However, when analyzed in a variety of readouts, ligands for a given 7TM receptor have been found to display distinct efficacy profiles, which cannot be accounted for by different amounts of a single active receptor conformation [4]. Data from fluorescence and spectroscopy studies have demonstrated that different ligands induce or stabilize different conformations of the receptor and modify receptor's interaction with G protein subunits [5, 6]. According to an alternative of the two-state model, heptahelical receptors may adopt several slightly different conformations, each with potentially different biochemical characteristics. Ligand stabilization of distinct receptor conformations, with different signaling properties, may allow the selective triggering of only a subset of the signaling capacity associated with the receptor activated by the endogenous related agonist [7]. This direction of the stimulus generated to a particular signaling pathway is called “stimulus trafficking” or “biased agonism” or “functional selectivity” [3, 8, 9]. The essential question is how the information contained in the ligand is conveyed, through receptor conformation change, to selective Gprotein coupling and effector signaling. Liapakis G et al. in their article provide the answer to this question by conceptualizing class A 7TMRs as allosteric proteins linked to intracellular components in a two way path. In one view, ligand binding to the receptor's pocket, stabilizes distinct active receptor conformations, which drive preferential recruitment and activation of certain effectors over others. In an alternative view, receptors in the membrane exist as preassembled complexes with G proteins and signaling partners [10]. Ligands selectively recognize specific receptor conformations present within signaling complexes of different composition [4]. In the inactive receptor conformation the transmembrane domains are arranged through a network of constraining intramolecular interactions, notably the “ionic lock”, which links the cytoplasmatic portions of transmembrane domains 3 (TM3) and 6 (TM6). Active states are achieved through disruption of ionic lock and subsequent separation of TM6 away from TM3, opening a G protein contact site in the cytoplasmic side of the 7TMR [11] and through a global toggle switch activation, with a vertical sew-saw inward movement of TM6 towards TM3 into the ligand binding pocket and outward movement of the intracellular end of TM6 opening for G-protein binding [11, 12]. In addition, interactions involve molecular microswitches, highly conserved residues with different interactions in the active vs. inactive states [12]. Novel methodologies, such as bioluminescence (BRET) or fluorescence (FRET) resonance energy transfer assays, based on labelling interacting signaling partners with energy donors or acceptors and measuring energy transfer between these intermolecular labels, have allowed the inference of spatial proximity between signalling components. Such approaches have permitted the monitoring of conformational changes in the components of signaling complexes and the study of spatiotemporal dynamics of the 7TMR signaling machinery in real time as analyzed elegantly by Denis C et al. in this issue....