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PKCɛ mediates substance P inhibition of GABAA receptors-mediated current in rat dorsal root ganglion

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Summary

The mechanism underlying the modulatory effect of substance P (SP) on GABA-activated response in rat dorsal root ganglion (DRG) neurons was investigated. In freshly dissociated rat DRG neurons, whole-cell patch-clamp technique was used to record GABA-activated current and sharp electrode intracellular recording technique was used to record GABA-induced membrane depolarization. Application of GABA (1–1000 μmol/L) induced an inward current in a concentration-dependent manner in 114 out of 127 DRG neurons (89.8 %) examined with whole-cell patch-clamp recordings. Bath application of GABA (1–1000 μmol/L) evoked a depolarizing response in 236 out of 257 (91.8%) DRG neurons examined with intracellular recordings. Application of SP (0.001–1 μmol/L) suppressed the GABA-activated inward current and membrane depolarization. The inhibitory effects were concentration-dependent and could be blocked by the selective neurokinin 1 (NK1) receptors antagonist spantide but not by L659187 and SR142801 (1 μmol/L, n=7), selective antagonists of NK2 and NK3. The inhibitory effect of SP was significantly reduced by the calcium chelator BAPTA-AM, phospholipase C (PLC) inhibitor U73122, and PKC inhibitor chelerythrine, respectively. The PKA inhibitor H-89 did not affect the SP effect. Remarkably, the inhibitory effect of SP on GABA-activated current was nearly completely removed by a selective PKCε inhibitor epilon-V1-2 but not by safingol and LY333531, selective inhibitors of PKCα and PKCβ. Our results suggest that NK1 receptor mediates SP-induced inhibition of GABA-activated current and membrane depolarization by activating intracellular PLC-Ca2+-PKCε cascade. SP might regulate the excitability of peripheral nociceptors through inhibition of the “pre-synaptic inhibition” evoked by GABA, which may explain its role in pain and neurogenic inflammation.

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Authors and Affiliations

  1. Department of Physiology, Medical College of Shihezi University, Shihezi, 832002, China

    Li Li  (李 丽), Lei Zhao  (赵 磊), Yang Wang  (王 洋), Ke-tao Ma  (马克涛), Wen-yan Shi  (石文艳) & Jun-qiang Si  (司军强)

  2. Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi University School of Medicine, Shihezi, 832002, China

    Li Li  (李 丽), Yang Wang  (王 洋), Ke-tao Ma  (马克涛), Wen-yan Shi  (石文艳), Ying-zi Wang  (王英姿) & Jun-qiang Si  (司军强)

  3. Basic Medical School of Wuhan University, Wuhan, 430071, China

    Yang Wang  (王 洋) & Jun-qiang Si  (司军强)

  4. Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jun-qiang Si  (司军强)

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  1. Li Li  (李 丽)
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  2. Lei Zhao  (赵 磊)
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  3. Yang Wang  (王 洋)
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  4. Ke-tao Ma  (马克涛)
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  5. Wen-yan Shi  (石文艳)
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  6. Ying-zi Wang  (王英姿)
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  7. Jun-qiang Si  (司军强)
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Corresponding author

Correspondence to Jun-qiang Si  (司军强).

Additional information

The authors contributed equally to this work.

This project was supported by grants from the National Natural Science Foundation of China (No. 30160026) and the Youth Science and Technology Innovation Special Foundation of Xinjiang Production and Construction Corps, China (No. 2010JC33).

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Li, L., Zhao, L., Wang, Y. et al. PKCɛ mediates substance P inhibition of GABAA receptors-mediated current in rat dorsal root ganglion. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 35, 1–9 (2015). https://doi.org/10.1007/s11596-015-1380-y

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  • DOI: https://doi.org/10.1007/s11596-015-1380-y

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