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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Developmental Biology - Cell Membrane Receptors

How Cell Membrane Receptors Are Activated

Possible new targets in treating major diseases...

There is a large, untapped potential for developing drugs against cancer, fibrosis and cardiovascular diseases by targeting a family of receptors known as Frizzled. Researchers at Karolinska Institutet in Sweden reveal in a new study published in Science Signaling, online 4 December 2018, how these receptors are activated in the cell membrane and the processes they then trigger within the cell.

G protein-coupled receptors are one of the largest families of proteins, with some 800 in humans that have a wide range of physiological functions. These receptors sit in the cell membrane and are activated by messenger molecules such as adrenalin, dopamine, histamine and endorphin, which trigger a cascade of processes within the cell.
G protein-coupled receptors are involved in the progress of many diseases and are very common targets for drugs such as beta blockers, antihistamines, morphine and L-DOPA.

"Since this is a large family of receptors, there are still many attractive but still unexploited targets for the future treatment of cancer, cardiovascular disease, diabetes, fibrosis and neurodegenerative diseases," says Professor Gunnar Schulte at the Department of Physiology and Pharmacology at Karolinska Institute.
Professor Schulte is researching a group of G protein-coupled receptors called Frizzled, which are important for numerous processes, including fetal development.

Signaling via these receptors is also linked to a large number of diseases, including different forms of tumors. Currently no drug molecules exist in clinics that affect Frizzled receptors — even though they structurally resemble receptors already proven effective as targets for drug therapies.
The new study reveals that one receptor in the Frizzled family, Frizzled 5, could be targeted by drugs in the same way as are histamine, adrenaline or dopamine receptors.

Professor Schulte has conducted this research in collaboration with Uppsala University; SciLifeLab in Sweden; and research teams in Germany and Canada. The researchers along the way, developed a new method for screening substance libraries for new drug molecules. All of these new technologies give science a better idea of how G protein-coupled receptors, along with other receptors on the cell surface, become activated and which cellular processes they trigger. This information could prove vital in development of new drugs.

"This opens up completely new opportunities and concepts for developing drugs for cancer, fibrosis and cardiovascular diseases based on targeting Frizzled proteins," explains Shane Wright, first author of the study and doctoral student in Professor Schulte's research group at Karolinska Institute.
Work on G protein-coupled receptors was recognized by the Nobel Committee in 2012 awarding the Nobel Prize in Chemistry to Brian Kobilka and Robert Lefkowitz.

Frizzleds (FZDs) are a group of seven transmembrane–spanning (7TM) receptors that belong to class F of the G protein–coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD5) is one of the most studied class F GPCRs that promote the functional inactivation of the ?-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD5 has not been shown to activate heterotrimeric G proteins. Here, we show that FZD5 exhibited a conformational change after the addition of WNT-5A, which is reminiscent of class A and class B GPCR activation. In addition, we performed several live-cell imaging and spectrometric-based approaches, such as dual-color fluorescence recovery after photobleaching (dcFRAP) and resonance energy transfer (RET)–based assays that demonstrated that FZD5 activated G?q and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD5 is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.

Shane C. Wright, Maria Consuelo Alonso Cañizal, Tobias Benkel, Katharina Simon, Christian Le Gouill, Pierre Matricon, Yoon Namkung, Viktoria Lukasheva, Gabriele M. König, Stéphane A. Laporte, Jens Carlsson, Evi Kostenis, Michel Bouvier, Gunnar Schulte and Carsten Hoffmann.

The study was financed by Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Novo Nordisk Foundation, the Knut & Alice Wallenberg Foundation, the Engkvist Foundations, Marie Curie ITN WntsApp, the Swedish Society for Medical Research, the Science for Life Laboratory, Deutsche Forschungsgemeinschaft and the Canadian Institute for Health Research.

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Jan 17, 2019   Fetal Timeline   Maternal Timeline   News   News Archive

FZD5 (RED) or class F of G protein–coupled receptors, is a prototypical G protein-coupled receptor (GPCR) with the purpose of stimulating G protein activation and downstream signaling on a gene. Frizzled receptors when activated on the cell membrane (BLUE), begin processes within the cell.

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