EJE AWARD 2020: Signalling by G protein-coupled receptors: why space and time matter

Abstract

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and major drug targets. They play a fundamental role in the endocrine system, where they mediate the effects of several hormones and neurotransmitters. As a result, alterations of GPCR signalling are a major cause of endocrine disorders such as congenital hypothyroidism or Cushing’s syndrome. My group develops innovative optical methods such as fluorescence resonance energy transfer (FRET) and single-molecule microscopy, which allow us to investigate GPCR signalling in living cells with unprecedented spatiotemporal resolution. Using this innovative approach, we have contributed to elucidate some long debated questions about the mechanisms of GPCR signalling and their involvement in human disease. Among other findings, these studies have led to the unexpected discovery that GPCRs are not only signalling at the cell surface, as previously assumed, but also at various intracellular sites. This has important implications to understand how hormones and neurotransmitters produce specific responses in our cells and might pave the way to innovative treatments for common diseases like diabetes or heart failure.

Call for Papers for a Virtual Special Issue on GPCR Signaling

“…G protein-dependent signaling was believed to occur only at the plasma membrane but the view is now held that GPCRs are also capable of signaling at various intracellular sites following internalization. 15 While the research community is still at the start of understanding the pharmacological impact of GPCR signaling at intracellular sites, growing evidence suggests that it may have important physiological consequences. In the near future, subcellular compartmentalized GPCR signaling may become therapeutically exploitable for the development of new modalities with increased selectivity and efficacy.…”

“…A long-debated question in the field was how to explain the high specificity observed in GPCR signaling, despite the fact that all GPCRs converge onto a few common signaling pathways. G protein-dependent signaling was believed to occur only at the plasma membrane but the view is now held that GPCRs are also capable of signaling at various intracellular sites following internalization . While the research community is still at the start of understanding the pharmacological impact of GPCR signaling at intracellular sites, growing evidence suggests that it may have important physiological consequences.…”

Interplay of Cholesterol and Actin in Neurotransmitter GPCR Signaling: Insights from Chronic Cholesterol Depletion Using Statin

“…G protein-coupled receptors (GPCRs) are the largest and most diverse class of seven-transmembrane domain-membrane proteins ubiquitously present in eukaryotes. − They carry out a range of signal transduction processes across the plasma membrane as a result of binding to various extracellular ligands. The ligand binding events are followed by coordinated structural changes in their transmembrane and extramembranous regions, which lead to relay of signals to the cellular interior. − Since signaling by GPCRs is involved in a large number of physiological processes ranging from development to cancer; they serve as major drug targets in all clinical areas. − Although traditionally, GPCR signaling was viewed as a chain of events initiated from the plasma membrane, recent evidence suggests that internalized pool of GPCRs could also mediate signaling that is different from that on the plasma membrane. − This further opens up new opportunities to develop novel therapeutic approaches to target GPCRs. , The serotonin 1A receptor is an important neurotransmitter receptor in the GPCR superfamily, which modulates a multitude of neurological, behavioral, and cognitive functions − and is a prominent drug target for treating neuropsychiatric disorders and even cancer. , …”

A new paradigm of intracrine free fatty acid receptor 4 signaling at lipid droplets

“…In parallel, although originally believed to be active only at the plasma membrane, evidence accumulated over the past 15 years indicates that GPCRs can also signal via G proteins from intracellular sites such as early endosomes or the Golgi/trans-Golgi network to locally control cellular functions [3][4][5][6][7][8] . Given the emerging paradigm of GPCR signaling at intracellular sites and the compartmentalized nature of intracellular metabolism 9,10 , an intriguing hypothesis is that metabolite-sensing GPCRs might signal from intracellular membranes in order to locally regulate metabolic pathways.…”