Human sensory neuron-specific Mas-related G protein-coupled receptors-X1 sensitize and directly activate transient receptor potential cation channel V1 via distinct signaling pathways

J Biol Chem. 2012 Nov 30;287(49):40956-71. doi: 10.1074/jbc.M112.408617. Epub 2012 Oct 16.


Sensory neuron-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are primate-specific proteins that are exclusively expressed in primary sensory neurons and provoke pain in humans. Hence, MRGPR-X1 represent promising targets for future pain therapy, but signaling pathways activated by MRGPR-X1 are poorly understood. The transient receptor potential cation channel V1 (TRPV1) is also expressed in primary sensory neurons and detects painful stimuli such as protons and heat. G(q)-promoted signaling has been shown to sensitize TRPV1 via protein kinase C (PKC)-dependent phosphorylation. In addition, recent studies suggested TRPV1 activation via a G(q)-mediated mechanism involving diacylglycerol (DAG) or phosphatidylinositol-4,5-bisphosphate (PIP(2)). However, it is not clear if DAG-promoted TRPV1 activation occurs independently from classic TRPV1 activation modes induced by heat and protons. Herein, we analyzed putative functional interactions between MRGPR-X1 and TRPV1 in a previously reported F11 cell line stably over-expressing MRGPR-X1. First, we found that MRGPR-X1 sensitized TRPV1 to heat and protons in a PKC-dependent manner. Second, we observed direct MRGPR-X1-mediated TRPV1 activation independent of MRGPR-X1-induced Ca(2+)-release and PKC activity or other TRPV1 affecting enzymes such as lipoxygenase, extracellular signal-regulated kinases-1/2, sarcoma, or phosphoinositide 3-kinase. Investigating several TRPV1 mutants, we observed that removal of the TRPV1 binding site for DAG and of the putative PIP(2) sensor decreased MRGPR-X1-induced TRPV1 activation by 71 and 43%, respectively. Therefore, we demonstrate dual functional interactions between MRGPR-X1 and TRPV1, resulting in PKC-dependent TRPV1 sensitization and DAG/PIP(2)-mediated activation. The molecular discrimination between TRPV1 sensitization and activation may help improve the specificity of current pain therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Cell Line
  • Chronic Pain / drug therapy
  • Diglycerides / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Proteins / metabolism*
  • Gene Expression Regulation*
  • Genetic Vectors
  • Humans
  • Manganese / pharmacology
  • Mice
  • Neurons / metabolism*
  • Pain Management
  • Phosphatidylinositols / metabolism
  • Protein Kinase C / metabolism
  • Rats
  • Receptors, G-Protein-Coupled / metabolism*
  • Sensory Receptor Cells / metabolism*
  • Signal Transduction
  • TRPV Cation Channels / metabolism*


  • Analgesics
  • Diglycerides
  • Enzyme Inhibitors
  • MrgC11 protein, mouse
  • Phosphatidylinositols
  • Receptors, G-Protein-Coupled
  • TRPV Cation Channels
  • TRPV1 protein, human
  • TRPV1 protein, mouse
  • Trpv1 protein, rat
  • mas-related gene-X1 receptor, human
  • sensory neuron-specific receptor 1, rat
  • Manganese
  • Protein Kinase C
  • GTP-Binding Proteins