Diacylglycerol kinases regulate TRPV1 channel activity

J Biol Chem. 2020 Jun 12;295(24):8174-8185. doi: 10.1074/jbc.RA119.012505. Epub 2020 Apr 28.


The transient receptor potential vanilloid 1 (TRPV1) channel is activated by heat and by capsaicin, the pungent compound in chili peppers. Calcium influx through TRPV1 has been shown to activate a calcium-sensitive phospholipase C (PLC) enzyme and to lead to a robust decrease in phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] levels, which is a major contributor to channel desensitization. Diacylglycerol (DAG), the product of the PLC-catalyzed PI(4,5)P2 hydrolysis, activates protein kinase C (PKC). PKC is known to potentiate TRPV1 activity during activation of G protein-coupled receptors, but it is not known whether DAG modulates TRPV1 during desensitization. We found here that inhibition of diacylglycerol kinase (DAGK) enzymes reduces desensitization of native TRPV1 in dorsal root ganglion neurons as well as of recombinant TRPV1 expressed in HEK293 cells. The effect of DAGK inhibition was eliminated by mutating two PKC-targeted phosphorylation sites, Ser-502 and Ser-800, indicating involvement of PKC. TRPV1 activation induced only a small and transient increase in DAG levels, unlike the robust and more sustained increase induced by muscarinic receptor activation. DAGK inhibition substantially increased the DAG signal evoked by TRPV1 activation but not that evoked by M1 muscarinic receptor activation. Our results show that Ca2+ influx through TRPV1 activates PLC and DAGK enzymes and that the latter limits formation of DAG and negatively regulates TRPV1 channel activity. Our findings uncover a role of DAGK in ion channel regulation.

Keywords: DAGK; PKC; TRPV1; calcium; diacylglycerol; dorsal root ganglia; phosphoinositide; transient receptor potential channels (TRP channels).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Capsaicin / pharmacology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cytoplasm / metabolism
  • Diacylglycerol Kinase / antagonists & inhibitors
  • Diacylglycerol Kinase / metabolism*
  • Diglycerides / metabolism
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / drug effects
  • Mice, Inbred C57BL
  • Models, Biological
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Ritanserin / pharmacology
  • TRPV Cation Channels / metabolism*


  • Diglycerides
  • Phosphatidylinositol 4,5-Diphosphate
  • Protein Kinase Inhibitors
  • TRPV Cation Channels
  • TRPV1 receptor
  • Ritanserin
  • Diacylglycerol Kinase
  • Protein Kinase C
  • Capsaicin
  • Calcium