Brain Advance Access originally published online on March 20, 2008
Brain 2008 131(5):1241-1251; doi:10.1093/brain/awn060
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Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain
1Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, 2Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo 650-8530, Japan, 3Institute for Biomedical Sciences of Pain, Capital Medical University, Beijing 100069, P.R. China and 4Section of Cell Signaling, Okazaki institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan
Correspondence to: Koichi Noguchi, MD, PhD, Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan E-mail: noguchi{at}hyo-med.ac.jp
Bradykinin is an inflammatory mediator that plays a pivotal role in pain and hyperalgesia in inflamed tissues by exciting and/or sensitizing nociceptors. TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain. Here, using electrophysiological, immunocytochemical and behavioural analyses, we showed a functional interaction of these two inflammation-related molecules in both heterologous expressing systems and primary sensory neurons. We found that bradykinin increased the TRPA1 currents evoked by allyl isothiocyanate (AITC) or cinnamaldehyde in HEK293 cells expressing TRPA1 and bradykinin receptor 2 (B2R). This potentiation was inhibited by phospholipase C (PLC) inhibitor or protein kinase A (PKA) inhibitor, and mimicked by PLC or PKA activator. The functional interaction between B2R and TRPA1, as well as the modulation mechanism, was also observed in rat dorsal root ganglia neurons. In an occlusion experiment, the PLC activator could enhance AITC-induced TRPA1 current further even in saturated PKA-mediated potentiation, indicating the additive potentiating effects of the PLC and PKA pathways. These data for the first time indicate that a cAMP-PKA signalling is involved in the downstream from B2R in dorsal root ganglia neurons in addition to PLC. Finally, subcutaneous pre-injection of a sub-inflammatory dose of bradykinin into rat hind paw enhanced AITC-induced pain behaviours, which was consistent with the observations in vitro. Collectively, these results represent a novel mechanism through which bradykinin released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.
Key Words: TRPA1; bradykinin; PLC; PKA; inflammation
Abbreviations: AC, adenylate cyclase; AITC, allyl isothiocyanate; BK, bradykinin; Cap, capsaicin; DAG, diacylglycerol; DMEM, Dulbecco's Modified Eagle's Medium; DRG, dorsal root ganglia; EBSS, Earle's balanced salt solution; FBS, foetal bovine serum; FSK, Forskolin; GF, GF109203X; HEK, human embryonic kidney-derived; IP3, inositol triphosphate; PIP2, phosphatidylinositol-4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PMA, phorbol 12-myristate 13-acetate; TRP, transient receptor potential
Received October 13, 2007. Revised January 17, 2008. Accepted March 1, 2008.
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