title: The C-type natriuretic peptide induces thermal hyperalgesia through a noncanonical Gβγ-dependent modulation of TRPV1 channel.
abstract: Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain essentially unknown. Many biological effects of NPs are mediated by guanylate cyclase (GC)-coupled NP receptors, NPR-A and NPR-B, whereas the third NP receptor, NPR-C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR-C can couple to specific Gα(i)-Gβγ-mediated intracellular signaling cascades in numerous cell types. We found that NPR-C is coexpressed in transient receptor potential vanilloid-1 (TRPV1)-expressing mouse dorsal root ganglia (DRG) neurons. NPR-C can be coimmunoprecipitated with Gα(i), and C-type natriuretic peptide (CNP) treatment induced translocation of protein kinase Cε (PKCε) to the plasma membrane of these neurons, which was inhibited by pertussis toxin pretreatment. Application of CNP potentiated capsaicin- and proton-activated TRPV1 currents in cultured mouse DRG neurons and increased their firing frequency, an effect that was absent in DRG neurons from TRPV1(-/-) mice. CNP-induced sensitization of TRPV1 activity was attenuated by pretreatment of DRG neurons with the specific inhibitors of Gβγ, phospholipase C-β (PLCβ), or PKC, but not of protein kinase A, and was abolished by mutations at two PKC phosphorylation sites in TRPV1. Furthermore, CNP injection into mouse hindpaw led to the development of thermal hyperalgesia that was attenuated by administration of specific inhibitors of Gβγ or TRPV1 and was also absent in TRPV1(-/-) mice. Thus, our work identifies the Gβγ-PLCβ-PKC-dependent potentiation of TRPV1 as a novel signaling cascade recruited by CNP in mouse DRG neurons that can lead to enhanced nociceptor excitability and thermal hypersensitivity.
authors.affiliation: Department of Pharmacology, Roy J. and Lucile A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Lipin
authors.initials: L
authors.lastname: Loo
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Shepherd
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Mickle
authors.forename: Ramón A
authors.initials: RA
authors.lastname: Lorca
authors.forename: Leonid P
authors.initials: LP
authors.lastname: Shutov
authors.forename: Yuriy M
authors.initials: YM
authors.lastname: Usachev
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D044387:GTP-Binding Protein beta Subunits / Q000502:physiology*; D044388:GTP-Binding Protein gamma Subunits / Q000502:physiology*; D005727:Ganglia, Spinal / Q000378:metabolism; D057809:HEK293 Cells; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020098:Natriuretic Peptide, C-Type / Q000502:physiology*; D051381:Rats; D050916:TRPV Cation Channels / Q000172:deficiency / Q000502:physiology*
chemical_list: D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D020098:Natriuretic Peptide, C-Type