title: Activation of TRPV1 channels inhibits mechanosensitive Piezo channel activity by depleting membrane phosphoinositides.
abstract: Capsaicin is an activator of the heat-sensitive TRPV1 (transient receptor potential vanilloid 1) ion channels and has been used as a local analgesic. We found that activation of TRPV1 channels with capsaicin either in dorsal root ganglion neurons or in a heterologous expression system inhibited the mechanosensitive Piezo1 and Piezo2 channels by depleting phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and its precursor phosphatidylinositol 4-phosphate [PI(4)P] from the plasma membrane through Ca(2+)-induced phospholipase Cδ (PLCδ) activation. Experiments with chemically inducible phosphoinositide phosphatases and receptor-induced activation of PLCβ indicated that inhibition of Piezo channels required depletion of both PI(4)P and PI(4,5)P2. The mechanically activated current amplitudes decreased substantially in the excised inside-out configuration, where the membrane patch containing Piezo1 channels is removed from the cell. PI(4,5)P2 and PI(4)P applied to these excised patches inhibited this decrease. Thus, we concluded that Piezo channel activity requires the presence of phosphoinositides, and the combined depletion of PI(4,5)P2 and PI(4)P reduces channel activity. In addition to revealing a role for distinct membrane lipids in mechanosensitive ion channel regulation, these data suggest that inhibition of Piezo2 channels may contribute to the analgesic effect of capsaicin.
authors: Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors: Istvan
authors: I
authors: Borbiro
authors: Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors: Doreen
authors: D
authors: Badheka
authors: Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. tibor.rohacs@rutgers.edu.
authors: Tibor
authors: T
authors: Rohacs
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D005727:Ganglia, Spinal / Q000166:cytology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D054803:Phospholipase C delta / Q000378:metabolism; D018075:RNA, Complementary / Q000235:genetics; D050916:TRPV Cation Channels / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D007473:Ion Channels; C515204:PIEZO1 protein, human; C000589132:PIEZO2 protein, human; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D018075:RNA, Complementary; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C037178:phosphatidylinositol 4-phosphate; D054803:Phospholipase C delta; D002211:Capsaicin