Eicosapentaenoic acid enhances PIEZO2 inactivation and counteracts PIEZO2 gain of function mutations.

PIEZO2 is an essential mechanosensitive ion channel for touch discrimination, vibration, interoception, and proprioception. Mechanosensitive ion channels rely on membrane composition to transduce physical stimuli into electrical signals. Dietary fatty acids are among the membrane lipid components that dynamically regulate ion channel function. We have previously shown that when part of the plasma membrane, the polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (C20:5, EPA) decreases membrane rigidity and bending stiffness, while enhancing PIEZO1 inactivation. To determine if EPA could also modulate PIEZO2 channel function, we used electrophysiology, fatty acid supplementation, dietary intervention, and lipidomics in vitro and ex vivo. We found that EPA, when incorporated into the membrane, increased the inactivation of heterologously expressed PIEZO2 without significantly affecting the current magnitude or apparent activation threshold. Similarly, we measured an increase in PIEZO2 inactivation in rat and mouse dorsal root ganglia (DRG) neurons after EPA supplementation. Importantly, cultured DRG neurons from mice carrying the C. elegans FAT-1 enzyme (which converts ω-6 to ω-3 PUFAs) or fed for 4-12 weeks with an EPA-enriched diet displayed enhanced PIEZO2 inactivation when compared to neurons from control mice. Moreover, using a consecutive mechanical step protocol, we found that PIEZO2 slowly recovered from inactivation in DRG neurons supplemented with EPA, from fat-1 mice, or from mice fed with an EPA-enriched diet, when compared with the control. These results support the notion that EPA favors PIEZO2 non-conductive states. Gain-of-function PIEZO2 mutations causing Distal Arthrogryposis type 5 display decreased PIEZO2 inactivation and enhanced recovery from inactivation. We show that EPA supplementation restored the gating properties of Distal Arthrogryposis causing mutations to wild-type levels in vitro. Overall, our findings show that dietary fatty acids modulate PIEZO2 function and could be an effective strategy to ameliorate GOF PIEZO2-mediated diseases.