Prostaglandin Metabolite Activation of Ion Channel TRPA1 

Brandon Akers and Gina Story

Department of Anesthesiology, Washington University School of Medicine

Prostaglandins (PGs) are a large class of fatty acid-derived physiological mediators, some of which are part of the “inflammatory soup,” endogenous chemicals involved in causing the inflammatory response. For example, PGE₂ and PGI₂, stimulate and sensitize cutaneous sensory neurons to painful thermal, mechanical, and chemical stimuli. One mechanism whereby PGs sensitize these neurons is via modulation of “thermoTRPs,” a subset of ion channels activated by temperature belonging to the Transient Receptor Potential ion channel superfamily. One such channel, TRPA1, is activated by cold as well as pungent or “burning” compounds derived from cinnamon and mustard oil. To date, endogenous activators of TRPA1 have not been identified. However, my lab has discovered that 15-delta PGJ2, a metabolite of PGD₂, potently activates TRPA1. These lipid compounds have not yet been correlated with painful sensations. In fact, PGD₂ has largely been considered to mediate anti-inflammatory processes. We find that 15-delta PGJ2 induces pain when administered cutaneously and does so via a TRPA1-specific mechanism. These results were obtained through our combinatorial approach involving imaging, electrophysiology and mouse genetics. Finally, owing to the desensitizing property of the TRPA1 ion channel once it is activated, we hypothesize that 15-delta PGJ2 plays a homeostatic role and is a potential target for the development of a novel pain therapeutic.