PKCɛ mediates substance P inhibition of GABAA receptors-mediated current in rat dorsal root ganglion.
10.1007/s11596-015-1380-y
- Author:
Li LI
1
;
Lei ZHAO
;
Yang WANG
;
Ke-tao MA
;
Wen-yan SHI
;
Ying-zi WANG
;
Jun-qiang SI
Author Information
1. Department of Physiology, Medical College of Shihezi University, Shihezi, 832002, China, lily7588@163.com.
- Publication Type:Journal Article
- MeSH:
Animals;
Female;
Ganglia, Spinal;
physiology;
Male;
Patch-Clamp Techniques;
Protein Kinase C-epsilon;
metabolism;
Rats;
Rats, Sprague-Dawley;
Receptors, GABA-A;
physiology;
Signal Transduction;
Substance P;
physiology
- From:
Journal of Huazhong University of Science and Technology (Medical Sciences)
2015;35(1):1-9
- CountryChina
- Language:English
-
Abstract:
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.
