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FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs.

Wright SC, Cañizal MCA, Benkel T, Simon K, Le Gouill C, Matricon P, Namkung Y, Lukasheva V, König GM, Laporte SA, Carlsson J, Kostenis E, Bouvier M, Schulte G, Hoffmann C

Section of Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, S17165 Stockholm, Sweden.

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 β-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 Gαq 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.

Sci Signal 2018;11(559).

Pubmed ID: 30514810

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