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Developmental Biology - Cell Membrane Receptors
Caught At Work
The "hottest" targets for disease therapy are proteins on the cell membrane...
G protein-coupled receptors (GPCRs) dot a cell's surface membrane and are targets in treating diseases such as hypertension, asthma and Parkinson´s. These are sites where many hormones and neurotransmitters interact to regulate the activity within our cells. Around half of all currently prescribed drugs target GPCRs receptors to treat disease. An international team of scientists from the Universities of Würzburg, Birmingham and Wroclaw have now succeeded in obsering such initial interactions.
Publication in Nature
"We were able to show that receptors and G proteins preferentially meet at special sites on the cell membrane, which we call hot spots."
Davide Calebiro PhD, Institute of Pharmacology and Toxicology; Bio-Imaging Center/Rudolf Virchow Center, University of Würzburg, Germany; Institute of Metabolism and Systems Research, University of Birmingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, UK.
Although this article originally appeared in the journal Nature on September 2017, it was republished on December 19, 2018 with a publisher's correction to three equations in the Methods section under "statistics."
These observations were made possible using a highly sophisticated single-molecule microscope. The authors were also able to observe how receptors and G proteins usually remain in contact very briefly, most terminating contact in just one second.
Furthermore, scientists found the cytoskeleton underneath the cell membrane plays an important role in the formation of hot spots. The existence of these hot spots for receptor signaling had previously gone unrecognized.
Technological developments allow new insights
Davide Calebiro and his co-authors are convinced these hot spots exert important influence on receptor signaling by increasing speed and efficiency in activation of G protein — while at the same time allowing Gs-protein signals released to remain local. According to the researchers, the findings show how "apparently simple biological processes can be highly sophisticated when observed close-up".
"Currently used drugs can either activate or block receptors. In the future, it might be possible to precisely influence these processes by manipulating the mobility of receptors and G proteins on the cell membrane, or their interactions at hot spots."
Davide Calebiro
Abstract
A new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular sites has recently emerged, but the underlying mechanisms and functional consequences are insufficiently understood. Here, we show that upon internalization in thyroid cells, endogenous TSH receptors traffic retrogradely to the trans-Golgi network (TGN) and activate endogenous Gs-proteins in the retromer-coated compartment that brings them to the TGN. Receptor internalization is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN. Blocking receptor internalization, inhibiting PKA II/interfering with its Golgi/TGN localization, silencing retromer or disrupting Golgi/TGN organization all impair efficient TSH-dependent cAMP response element binding protein (CREB) phosphorylation. These results suggest that retrograde trafficking to the TGN induces local Gs-protein activation and cAMP/PKA signaling at a critical position near the nucleus, which appears required for efficient CREB phosphorylation and gene transcription. This provides a new mechanism to explain the functional consequences of GPCR signaling at intracellular sites and reveals a critical role for the TGN in GPCR signaling.
Authors
Amod Godbole, Sandra Lyga, Martin J. Lohse and Davide Calebiro.
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Jan 16, 2019 Fetal Timeline Maternal Timeline News News Archive
 Visualization and tracking of single receptors (GREEN) and G proteins (MAGENTA) as they interact on a living cell. Interactions occur at membrane "hot spots". Image by Team Calebiro.
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