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.
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.
Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München 80336 München, Germany.
Hans Jürgen
HJ
Solinski
Susanna
S
Zierler
Thomas
T
Gudermann
Andreas
A
Breit
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D059350:Chronic Pain / Q000188:drug therapy; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D008345:Manganese / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D059408:Pain Management; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000378:metabolism*
D000700:Analgesics; D004075:Diglycerides; D004791:Enzyme Inhibitors; D019204:GTP-Binding Proteins; D008345:Manganese; D010716:Phosphatidylinositols; D011493:Protein Kinase C; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C470192:Mrgprx1 protein, mouse; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; C510803:mas-related gene-X1 receptor, human; C000591603:Mrgprc protein, rat