The subcellular dynamics of GPCR signaling

摘要

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and mediate the effects of a multitude of extracellular cues, such as hormones, neurotransmitters, odorants and light. Because of their involvement in numerous physiological and pathological processes and their accessibility, they are extensively exploited as pharmacological targets. Biochemical and structural biology investigations have clarified the molecular basis of GPCR signaling to a high level of detail. In spite of this, how GPCRs can efficiently and precisely translate extracellular signals into specific and well-orchestrated biological responses in the complexity of a living cell or organism remains insufficiently understood. To explain the high efficiency and specificity observed in GPCR signaling, it has been suggested that GPCR might signal in discrete nanodomains on the plasma membrane or even form stable complexes with G proteins and effectors. However, directly testing these hypotheses has proven a major challenge. Recent studies taking advantage of innovative optical methods such as fluorescence resonance energy transfer (FRET) and single-molecule microscopy have begun to dig into the organization of GPCR signaling in living cells on the spatial (nm) and temporal (ms) scales on which cell signaling events are taking place. The results of these studies are revealing a complex and highly dynamic picture, whereby GPCRs undergo transient interaction with their signaling partners, membrane lipids and the cytoskeleton to form short-lived signaling nanodomains both on the plasma membrane and at intracellular sites. Continuous exchanges among such nanodomains via later diffusion as well as via membrane trafficking might provide a highly sophisticated way of controlling the timing and location of GPCR signaling. Here, we will review the most recent advances in our understanding of the organization of GPCR signaling in living cells, with a particular focus on its dynamics.