Temporal Bias: Time-Encoded Dynamic GPCR Signaling

Abstract

Evidence suggests that cells can time-encode signals for secure transport and perception of information, and it appears that this dynamic signaling is a common principle of nature to code information in time. G-protein-coupled receptor (GPCR) signaling networks are no exception as their composition and signal transduction appear temporally flexible. In this review, we discuss the potential mechanisms by which GPCRs code biological information in time to create ‘temporal bias.’ We highlight dynamic signaling patterns from the second messenger to the receptor–ligand level and shed light on the dynamics of G-protein cycles, the kinetics of ligand–receptor interaction, and the occurrence of distinct signaling waves within the cell. A dynamic feature such as temporal bias adds to the complexity of GPCR signaling bias and gives rise to the question whether this trait could be exploited to gain control over time-encoded cell physiology. Over the past years, the temporal dimension of signaling emerged as a discrete parameter of cell signaling and is referred to as dynamic signaling. Technical developments allowed the assessment of temporal bias, such as Single-cell and single-molecule fluorescent biosensors based on resonance energy transfer (FRET/BRET) for intra- and inter-molecular rearrangement and interaction, respectively, or protein-induced fluorescence enhancement (PIFE). Single-molecule tracking and fluorescence correlation spectroscopy (FCS). Optogenetic engineering of the cellular signaling machinery in vitro and in vivo as well as light-controlled chemistry. Electron paramagnetic resonance (EPR) and double electron-electron resonance spectroscopy (DEER). Real-time functional assays such as luminescence/fluorescence second messenger assays. Holistic cellular real-time assays, label-free optical (DMR) and electrical (CDS) techniques. High-content imaging systems/microscopy with improved temporal and spatial resolution. Computational methods (e.g., molecular dynamics simulations). These developments led to the introduction of several concepts that underlie kinetic aspects of GPCR signaling, such as kinetic scaffolding, ligand residence time, dwell times, frequency filters, oscillatory phenomena, signaling from internalized receptors and structural dynamics as signaling determinant. This prompted us to consider temporal bias as a kinetic quality beside physical and spatial quality as a category of signaling bias.