Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors

被引:46
|
作者
Alkhani, Hazim [1 ,2 ]
Ase, Ariel R. [1 ,2 ]
Grant, Rebecca [3 ]
O'Donnell, Dajan [3 ]
Groschner, Klaus [4 ]
Seguela, Philippe [1 ,2 ,5 ]
机构
[1] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada
[2] McGill Univ, Alan Edwards Res Ctr Pain, Montreal, PQ H3A 2B4, Canada
[3] AstraZeneca R&D, St Laurent, PQ, Canada
[4] Med Univ Graz, Inst Biophys, Graz, Austria
[5] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada
来源
MOLECULAR PAIN | 2014年 / 10卷
关键词
TRPC channel; Nucleotide; ATP; Protease; GPCR; Phospholipase C; Sensory neuron; Sensitization; DRG; Trigeminal; Inflammation; Pain; PROTEIN-KINASE-C; DORSAL-ROOT GANGLION; VANILLOID RECEPTOR-1; ACTIVATED RECEPTORS; SENSORY NEURONS; PKC-EPSILON; CHANNELS; PAIN; RAT; SENSITIZATION;
D O I
10.1186/1744-8069-10-43
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Background: Prolonged intracellular calcium elevation contributes to sensitization of nociceptors and chronic pain in inflammatory conditions. The underlying molecular mechanisms remain unknown but store-operated calcium entry (SOCE) components participate in calcium homeostasis, potentially playing a significant role in chronic pain pathologies. Most G protein-coupled receptors activated by inflammatory mediators trigger calcium-dependent signaling pathways and stimulate SOCE in primary afferents. The aim of the present study was to investigate the role of TRPC3, a calcium-permeable non-selective cation channel coupled to phospholipase C and highly expressed in DRG, as a link between activation of pro-inflammatory metabotropic receptors and SOCE in nociceptive pathways. Results: Using in situ hybridization, we determined that TRPC3 and TRPC1 constitute the major TRPC subunits expressed in adult rat DRG. TRPC3 was found localized exclusively in small and medium diameter sensory neurons. Heterologous overexpression of TRPC3 channel subunits in cultured primary DRG neurons evoked a significant increase of Gd3+-sensitive SOCE following thapsigargin-induced calcium store depletion. Conversely, using the same calcium add-back protocol, knockdown of endogenous TRPC3 with shRNA-mediated interference or pharmacological inhibition with the selective TRPC3 antagonist Pyr10 induced a substantial decrease of SOCE, indicating a significant role of TRPC3 in SOCE in DRG nociceptors. Activation of P2Y2 purinoceptors or PAR2 protease receptors triggered a strong increase in intracellular calcium in conditions of TRPC3 overexpression. Additionally, knockdown of native TRPC3 or its selective pharmacological blockade suppressed UTP-or PAR2 agonist-evoked calcium responses as well as sensitization of DRG neurons. These data show a robust link between activation of pro-inflammatory receptors and calcium homeostasis through TRPC3-containing channels operating both in receptor-and store-operated mode. Conclusions: Our findings highlight a major contribution of TRPC3 to neuronal calcium homeostasis in somatosensory pathways based on the unique ability of these cation channels to engage in both SOCE and receptor-operated calcium influx. This is the first evidence for TRPC3 as a SOCE component in DRG neurons. The flexible role of TRPC3 in calcium signaling as well as its functional coupling to pro-inflammatory metabotropic receptors involved in peripheral sensitization makes it a potential target for therapeutic strategies in chronic pain conditions.
引用
收藏
页数:12
相关论文
共 50 条
  • [31] Activation of ERK1/2 by Store-Operated Calcium Entry in Rat Parotid Acinar Cells
    Soltoff, Stephen P.
    Lannon, William A.
    PLOS ONE, 2013, 8 (08):
  • [32] Role of store-operated calcium entry in imperatorin-induced vasodilatation of rat small mesenteric artery
    Zhang, Yan
    Wang, Qun Li
    Zhan, Ying Zhuan
    Jie, Hai
    Cao, Yan Jun
    He, Lang Chong
    EUROPEAN JOURNAL OF PHARMACOLOGY, 2010, 647 (1-3) : 126 - 131
  • [33] Chlorpromazine inhibits store-operated calcium entry and subsequent noradrenaline secretion in PC12 cells
    Choi, SY
    Kim, YH
    Lee, YK
    Kim, KT
    BRITISH JOURNAL OF PHARMACOLOGY, 2001, 132 (02) : 411 - 418
  • [34] Peroxisome proliferator-activated receptor γ inhibits pulmonary hypertension targeting store-operated calcium entry
    Wang, Yingfeng
    Lu, Wenju
    Yang, Kai
    Wang, Yan
    Zhang, Jie
    Jia, Jing
    Yun, Xin
    Tian, Lichun
    Chen, Yuqin
    Jiang, Qian
    Zhang, Bo
    Chen, Xiuqing
    Wang, Jian
    JOURNAL OF MOLECULAR MEDICINE-JMM, 2015, 93 (03): : 327 - 342
  • [35] High cadmium exposure impairs adult hippocampal neurogenesis via disruption of store-operated calcium entry
    Li, Guoqing
    Sun, Caiyun
    Zhu, Le
    Zeng, Yan
    Li, Jinquan
    Mei, Yufei
    ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY, 2024, 286
  • [36] TRPC1 stimulates calcium-sensing receptor-induced store-operated Ca2+ entry and nitric oxide production in endothelial cells
    Qu, Yuan-Yuan
    Wang, La-Mei
    Zhong, Hua
    Liu, Yong-Min
    Tang, Na
    Zhu, Li-Ping
    He, Fang
    Hu, Qing-Hua
    MOLECULAR MEDICINE REPORTS, 2017, 16 (04) : 4613 - 4619
  • [37] Induction of store-operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
    Liu, Zhijun
    Wei, Yiju
    Zhang, Lei
    Yee, Patricia P.
    Johnson, Martin
    Zhang, Xuexin
    Gulley, Melissa
    Atkinson, Jennifer M.
    Trebak, Mohamed
    Wang, Hong-Gang
    Li, Wei
    ONCOGENE, 2019, 38 (01) : 120 - 139
  • [38] Complex Actions of Ionomycin in Cultured Cerebellar Astrocytes Affecting Both Calcium-Induced Calcium Release and Store-Operated Calcium Entry
    Mueller, Margit S.
    Obel, Linea F.
    Waagepetersen, Helle S.
    Schousboe, Arne
    Bak, Lasse K.
    NEUROCHEMICAL RESEARCH, 2013, 38 (06) : 1260 - 1265
  • [39] IP3 receptors and store-operated Ca2+ entry: a license to fill
    Taylor, Colin W.
    Machaca, Khaled
    CURRENT OPINION IN CELL BIOLOGY, 2019, 57 : 1 - 7
  • [40] RhoA enhances store-operated Ca2+ entry and intestinal epithelial restitution by interacting with TRPC1 after wounding
    Chung, Hee Kyoung
    Rathor, Navneeta
    Wang, Shelley R.
    Wang, Jian-Ying
    Rao, Jaladanki N.
    AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2015, 309 (09): : G759 - G767