PIEZO1 and PIEZO2 are non-selective cation channels activated by mechanical force. PIEZO2 is expressed in peripheral sensory neurons of the dorsal root ganglia (DRG) where it is indispensable for gentle touch and proprioception while also contributing to injury-induced mechanical pain in mice and humans. PIEZO1 has a broader expression profile and is involved in a variety of processes including blood and lymphatic vessel formation, red blood cell volume regulation, and epithelial cell division. Both PIEZO1 and PIEZO2 channels are inhibited by non-specific blockers of mechanically activated ion channels such as gadolinium, ruthenium red and GsMTx4. Screening small molecule libraries resulted in the discovery of selective activators of PIEZO1 channels (Yoda1, Jedi1, and Jedi2), but the same screens did not identify chemical activators of PIEZO2. Chemical modification of Yoda1 resulted in Dooku, a compound that antagonizes Yoda1 activation of PIEZO1.
Currently, there are no known endogenous or exogenous inhibitors that selectively inhibit PIEZO2 over PIEZO1. Various dietary fatty acids have been shown to modulate the activity of both PIEZO1 and PIEZO2 channels, but only one of those lipids showed selectivity for PIEZO1 over PIEZO2: the omega-3 docosahexaenoic acid (DHA) which increased the function of PIEZO1. The dietary saturated fatty acid margaric acid (C17:0) has been shown to inhibit both PIEZO1 and PIEZO2 activity, with a higher potency on PIEZO1. Linoleic acid (C18:2), an unsaturated dietary fatty acid on the other hand was shown to increase the activity of both PIEZO1 and PIEZO2. The omega-3 eicosapentanoic acid (EPA) decreased the inactivation time constant for wild-type and gain of function mutant PIEZO1 and PIEZO2 channels. Selective PIEZO2 inhibitors would be highly valuable research tools and would have substantial therapeutic potential against chronic pain more effectively.
Scientists at Rutgers New Jersey Medical School discovered now that the endogenous lipid phosphatidic acid an its can reduce the activity of certain touch-sensing ion channels in the body, according to a study published in Nature Communications. Researchers found that increasing the levels of phosphatidic acid in cells makes them less sensitive to touch. This finding was confirmed through experiments on sensory neurons and tests in mice, where the animals became more sensitive to touch when the formation of phosphatidic acid was inhibited. The lipids identified that inhibit PIEZO2 channels, phosphatidic acid, and LPA, both have a free phosphate group attached to the glycerol backbone. The only difference between these lipids is the presence of one vs. two acyl chains (LPA vs. phosphatidic acid, respectively). In the experiments, phosphatidic acid and LPA were sufficient to inhibit PIEZO2 channels indicating that the number of acyl chains is not a major determinant of the inhibitory effect.
The degree of unsaturation and length of LPA’s acyl-chain did not grossly affect LPA’s inhibition of PIEZO2. The free phosphate attached to the glycerol backbone, on the other hand, is important for PIEZO2 inhibition as phosphatidylglycerol and phosphatidylserine in which glycerol or serine are attached to the phosphate, did not inhibit the channel. Phosphatidic acid can also be generated by phospholipase D (PLD) enzymes that cleave the headgroup from phospholipids, mainly phosphatidylcholine, leaving the phosphate on the glycerol backbone and thus generating phosphatidic acid. In addition, the research team showed that optogenetic activation of PLD inhibits PIEZO2, but not PIEZO1, demonstrating that in principle PLD activity can influence PIEZO2 channel activity. Moreover, the PLD inhibitor FIPI increases mechanically activated PIEZO2, indicating that basal PLD activity modulates PIEZO2 activity. These informations might open new avenues for the tratment of chronic pain.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in CLinical Biochemistry.
Scientific references
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