Our lab's first Biorxiv deposition is live! We show that two commercially-available "aquaporin-4 inhibitors" do not inhibit aquaporin-4 as previously described. www.biorxiv.org/content/10.1... - ThreadSky

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kitchenphil.bsky.social • 87 days ago

Our lab's first Biorxiv deposition is live!

We show that two commercially-available "aquaporin-4 inhibitors" do not inhibit aquaporin-4 as previously described.

https://www.biorxiv.org/content/10.1101/2024.12.04.625365v1

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kitchenphil.bsky.social•87 days ago

We initially became interested in TGN-020 and AER-270 as positive controls in a screen for novel aquaporin-4 modulators. To our surprise, they were not functional in assays using mammalian cell lines overexpressing aquaporin-4, nor in primary astrocytes.

kitchenphil.bsky.social•87 days ago

We tested AER-270 and TGN-020 using recombinant AQP4 protein reconstituted into proteoliposomes and again found no inhibitory effect.

kitchenphil.bsky.social•87 days ago

We then went back to the “gold standard” Xenopus laevis oocyte swelling assay and found apparent inhibitory effects, consistent with the existing literature.

kitchenphil.bsky.social•87 days ago

There are several other examples of “aquaporin-4 inhibitors” in the literature that appear to inhibit aquaporin-4 in the Xenopus assay but not in any other assay system, including acetazolamide, and various antiepileptics and loop diuretics.

kitchenphil.bsky.social•87 days ago

We conclude that the Xenopus assay is susceptible to false positive hits. Using a proteomics-based target identification method, we found 30 common targets of TGN-020 and AER-270 in Xenopus oocytes which could plausibly explain this.

kitchenphil.bsky.social•87 days ago

We further report a variety of off-target effects of these compounds. AER-270 inhibited carbonic anhydrase and NF-kB signalling via IKKB with downstream effects on AQP4 gene expression.

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