title: Peripheral pain is enhanced by insulin-like growth factor 1 through a G protein-mediated stimulation of T-type calcium channels.
abstract: Insulin-like growth factor 1 (IGF-1) is implicated in the nociceptive (pain) sensitivity of primary afferent neurons. We found that the IGF-1 receptor (IGF-1R) functionally stimulated voltage-gated T-type Ca(2+) (CaV3) channels in mouse dorsal root ganglia (DRG) neurons through a mechanism dependent on heterotrimeric G protein (heterotrimeric guanine nucleotide-binding protein) signaling. IGF-1 increased T-type channel currents in small-diameter DRG neurons in a manner dependent on IGF-1 concentration and IGF-1R but independent of phosphatidylinositol 3-kinase (PI3K). The intracellular subunit of IGF-1R coimmunoprecipitated with Gαo. Blocking G protein signaling by the intracellular application of guanosine diphosphate (GDP)-β-S or with pertussis toxin abolished the stimulatory effects of IGF-1. Antagonists of protein kinase Cα (PKCα), but not of PKCβ, abolished the IGF-1-induced T-type channel current increase. Application of IGF-1 increased membrane abundance of PKCα, and PKCα inhibition (either pharmacologically or genetically) abolished the increase in T-type channel currents stimulated by IGF-1. IGF-1 increased action potential firing in DRG neurons and increased the sensitivity of mice to both thermal and mechanical stimuli applied to the hindpaw, both of which were attenuated by intraplantar injection of a T-type channel inhibitor. Furthermore, inhibiting IGF-1R signaling or knocking down CaV3.2 or PKCα in DRG neurons abolished the increased mechanical and thermal sensitivity that mice exhibited under conditions modeling chronic hindpaw inflammation. Together, our results showed that IGF-1 enhances T-type channel currents through the activation of IGF-1R that is coupled to a G protein-dependent PKCα pathway, thereby increasing the excitability of DRG neurons and the sensitivity to pain.
authors.affiliation: Department of Neurobiology, Medical College of Soochow University, Suzhou 215123, P.R. China. Department of Geriatrics, Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou 215004, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Geriatrics, Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou 215004, P.R. China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xingjun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Gong
authors.affiliation: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. taoj@suda.edu.cn yangang.sun@ion.ac.cn.
authors.forename: Yan-Gang
authors.initials: YG
authors.lastname: Sun
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
authors.affiliation: Department of Neurobiology, Medical College of Soochow University, Suzhou 215123, P.R. China.
authors.forename: Xinghong
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Neurobiology, Medical College of Soochow University, Suzhou 215123, P.R. China. taoj@suda.edu.cn yangang.sun@ion.ac.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002458:Cell Fractionation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008856:Microscopy, Fluorescence; D009475:Neurons, Afferent / Q000378:metabolism*; D010146:Pain / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017933:Peripheral Nervous System / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013697:Thermosensing / Q000187:drug effects
chemical_list: D020747:Calcium Channels, T-Type; D034741:RNA, Small Interfering; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051571:Protein Kinase C-alpha; D019204:GTP-Binding Proteins