The Tunicate Metabolite 2‑(3,5-Diiodo-4-methoxyphenyl)ethan-1-amine Targets Ion Channels of Vertebrate Sensory Neurons

• Published in: ACS chemical biology Vol. 16; no. 9; pp. 1654 - 1662
• Main Authors: Paguigan, Noemi D, Yan, Yannan, Karthikeyan, Manju, Chase, Kevin, Carter, Jackson, Leavitt, Lee S, Lim, Albebson L, Lin, Zhenjian, Memon, Tosifa, Christensen, Sean, Bentzen, Bo H, Schmitt, Nicole, Reilly, Christopher A, Teichert, Russell W, Raghuraman, Shrinivasan, Olivera, Baldomero M, Schmidt, Eric W
• Format: Journal Article
• Language: English
• Published: American Chemical Society 17-09-2021
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.1c00328

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 intracellular calcium concentration [Ca2+]i of low-threshold cold thermosensors. When injected into mice, DIMTA increased the threshold of cold sensation by >3 °C. 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.