Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate Gα_q/11-Mediated Signaling Pathways

The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are natural products, which inhibit heterotrimeric Gα_q/11 proteins with high potency and outstanding selectivity. Historically, pharmacological modulation of Gα proteins was only achieved by treatment with pertussis toxin and cholera toxin, whose application can be tedious and is restricted to the inhibition of Gα_i/o proteins and activation of Gα_s proteins, respectively. The breakthrough discovery and characterization of YM and FR rendered the closely related Gα_q, Gα₁₁, and Gα₁₄ proteins amenable to pharmacological inhibition, and since then, both compounds have become widely used in molecular pharmacology and were also proven to be efficacious in animal models of disease. In the past years, both YM and FR were thoroughly characterized and have substantially contributed to an improved understanding of Gα_q/11 signaling on a molecular and cellular level. Yet, the possibilities to interrogate Gα_q/11 signaling in complex systems have only been exploited in a very limited number of studies, whose promising initial results warrant further application of YM and FR in basic and translational research. As both compounds have become commercially available as of late, this review focuses on their application in cell-based assays and in vivo systems, highlighting their qualities as tool compounds and providing instructions for their use.