Transient receptor potential canonical 3 (TRPC3) is required for IgG immune complex-induced excitation of the rat dorsal root ganglion neurons.
Chronic pain may accompany immune-related disorders with an elevated level of serum IgG immune complex (IgG-IC), but the underlying mechanisms are obscure. We previously demonstrated that IgG-IC directly excited a subpopulation of dorsal root ganglion (DRG) neurons through the neuronal Fc-gamma receptor I (FcγRI). This might be a mechanism linking IgG-IC to pain and hyperalgesia. The purpose of this study was to investigate the signaling pathways and transduction channels activated downstream of IgG-IC and FcγRI. In whole-cell recordings, IgG-IC induced a nonselective cation current (I(IC)) in the rat DRG neurons, carried by Ca(2+) and Na(+). The I(IC) was potentiated or attenuated by, respectively, lowering or increasing the intracellular Ca(2+) buffering capacity, suggesting that this current was regulated by intracellular calcium. Single-cell RT-PCR revealed that transient receptor potential canonical 3 (TRPC3) mRNA was always coexpressed with FcγRI mRNA in the same DRG neuron. Moreover, ruthenium red (a general TRP channel blocker), BTP2 (a general TRPC channel inhibitor), and pyrazole-3 (a selective TRPC3 blocker) each potently inhibited the I(IC). Specific knockdown of TRPC3 using small interfering RNA attenuated the IgG-IC-induced Ca(2+) response and the I(IC). Additionally, the I(IC) was blocked by the tyrosine kinase Syk inhibitor OXSI-2, the phospholipase C (PLC) inhibitor neomycin, and either the inositol triphosphate (IP(3)) receptor antagonist 2-aminoethyldiphenylborinate or heparin. These results indicated that the activation of neuronal FcγRI triggers TRPC channels through the Syk-PLC-IP(3) pathway and that TRPC3 is a key molecular target for the excitatory effect of IgG-IC on DRG neurons.
Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Lintao
L
Qu
Yumei
Y
Li
Xinghua
X
Pan
Pu
P
Zhang
Robert H
RH
LaMotte
Chao
C
Ma
D000083:Acetanilides / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D002412:Cations / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology*; D007074:Immunoglobulin G / Q000276:immunology* / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017452:Receptors, IgG / Q000378:metabolism; D012430:Ruthenium Red / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018709:Statistics, Nonparametric; D050052:TRPC Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology; D014162:Transfection
C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000083:Acetanilides; D000813:Anilides; D002412:Cations; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D011687:Purines; D034741:RNA, Small Interfering; D017452:Receptors, IgG; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D013830:Thiadiazoles; D012430:Ruthenium Red; D004533:Egtazic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium