Description:
<jats:p>Small molecular chemicals that target individual subtype of G proteins including Gs, Gi and Gq has been lacking, except for pertussis toxin that has been validated as a selective peptide inhibitor of the Gi protein. Recently, a cyclic depsipeptide compound termed YM‐254890 was isolated from the culture broth of Chromobacterium sp., which was reported as a selective inhibitor for the Gq protein by blocking GDP exchange of GTP on the α subunit of Gq complex; however, functional selectivity of YM‐254890 towards various G proteins remains unclear, primarily due to its restricted availability before 2017. Here, using primary human coronary artery endothelial cells (HCAEC) as a testing model, we performed a systemic pharmacological study on the functional selectivity of YM‐254890 on multiple G protein‐mediated receptor signaling. First, we confirmed that YM‐254890, at 30 nM, abolished 100 μM UTP activated P2Y2 receptor‐mediated Ca<jats:sup>2+</jats:sup> signaling, indicating its potent inhibition on the Gq protein. However, unexpectedly, pretreatment of HCAEC with 30 nM YM‐254890 also significantly suppressed (>50%) 100 μM adenosine‐induced cAMP elevation by Gs‐coupled adenosine A2 receptors; furthermore, we found that 30 nM YM‐254890 significantly reversed CXCL12 activated CXCR4‐Gi protein mediated suppression of cellular cAMP level, suggesting a blockage of Gi proteins. Western blotting assay indicated that YM‐254890, at 30 nM, abolished MAPK signaling triggered by P2Y2, CXCR4 and adenosine A2 receptors. Nonetheless, no cellular toxicity was observed for YM‐254890 up to 1 μM, and it neither affected A23187‐induced Ca<jats:sup>2+</jats:sup> signaling, nor forskolin‐induced cAMP elevation and growth factor‐induced MAPK signaling. We conclude that YM‐254890 is not a selective inhibitor for the Gq protein, instead it acts as a broader spectrum inhibitor for Gq, Gs and Gi with a high potency, without affecting non‐GPCR‐mediated cellular signaling.</jats:p><jats:p><jats:bold>Support or Funding Information</jats:bold></jats:p><jats:p>Supported in part by NIH grant 1R01HL125279‐01A1 (to J.S.)</jats:p><jats:p>This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in <jats:italic>The FASEB Journal</jats:italic>.</jats:p>