The tunicate metabolite 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine targets ion channels of vertebrate sensory neurons

Paguigan, N. D.; Yan, Y.; Karthikeyan, M.; Chase, K.; Carter, J.; Leavitt, L. S.; Lim, A. L.; Lin, Z.; Memon, T.; Christensen, S. B.; Bentzen, B. H.; Schmitt, N.; Reilly, C. A.; Teichert, R. W.; Raghuraman, S.; Olivera, B. M.; Schmidt, E. W.

doi:10.1101/2021.05.05.442828

bioRxiv · 10.1101/2021.05.05.442828

The tunicate metabolite 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine targets ion channels of vertebrate sensory neurons

Paguigan, N. D.·Yan, Y.·Karthikeyan, M.·Chase, K.·Carter, J.·Leavitt, L. S.·Lim, A. L.·Lin, Z.·Memon, T.·Christensen, S. B.·Bentzen, B. H.·Schmitt, N.·Reilly, C. A.·Teichert, R. W.·Raghuraman, S.·Olivera, B. M.·Schmidt, E. W.

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Abstract

Marine tunicates produce defensive amino-acid derived metabolites, including 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine (DIMTA), but their mechanisms of action are rarely known. Using an assay-guided approach, we found that out of the many different sensory cells in the mouse dorsal root ganglion (DRG), DIMTA selectively affected low-threshold cold thermosensors. Whole-cell electrophysiology experiments using DRG cells, channels expressed in Xenopus oocytes and human cell lines revealed that DIMTA blocks several potassium channels, reducing the magnitude of the afterhyperpolarization and increasing the baseline [Ca2+]i of low-threshold cold thermosensors. When injected into mice, DIMTA increased the threshold of cold sensation by >3 oC. DIMTA may thus serve as a lead in the further design of compounds that inhibit problems in the cold-sensory system, such as cold allodynia and other neuropathic pain conditions.

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Paguigan, N. D., Yan, Y., Karthikeyan, M., Chase, K., Carter, J., Leavitt, L. S., Lim, A. L., Lin, Z., Memon, T., Christensen, S. B., Bentzen, B. H., Schmitt, N., Reilly, C. A., Teichert, R. W., Raghuraman, S., Olivera, B. M., Schmidt, E. W.. 2021-05-05. The tunicate metabolite 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine targets ion channels of vertebrate sensory neurons. https://doi.org/10.1101/2021.05.05.442828

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