title: PKCɛ mediates substance P inhibition of GABAA receptors-mediated current in rat dorsal root ganglion.
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.
authors: Department of Physiology, Medical College of Shihezi University, Shihezi, 832002, China.|Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi University School of Medicine, Shihezi, 832002, China.
authors: Li
authors: L
authors: Li
authors: Department of Physiology, Medical College of Shihezi University, Shihezi, 832002, China.
authors: Lei
authors: L
authors: Zhao
authors: Department of Physiology, Medical College of Shihezi University, Shihezi, 832002, China.|Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi University School of Medicine, Shihezi, 832002, China.|Basic Medical School of Wuhan University, Wuhan, 430071, China.
authors: Yang
authors: Y
authors: Wang
authors: Department of Physiology, Medical College of Shihezi University, Shihezi, 832002, China.|Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi University School of Medicine, Shihezi, 832002, China.
authors: Ke-Tao
authors: KT
authors: Ma
authors: Department of Physiology, Medical College of Shihezi University, Shihezi, 832002, China.|Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi University School of Medicine, Shihezi, 832002, China.
authors: Wen-Yan
authors: WY
authors: Shi
authors: Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi University School of Medicine, Shihezi, 832002, China.
authors: Ying-Zi
authors: YZ
authors: Wang
authors: Department of Physiology, Medical College of Shihezi University, Shihezi, 832002, China. sijunqiang11@hotmail.com.|Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi University School of Medicine, Shihezi, 832002, China. sijunqiang11@hotmail.com.|Basic Medical School of Wuhan University, Wuhan, 430071, China. sijunqiang11@hotmail.com.|Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. sijunqiang11@hotmail.com.
authors: Jun-Qiang
authors: JQ
authors: Si
mesh_terms: D000818:Animals; D005260:Female; D005727:Ganglia, Spinal / Q000502:physiology*; D008297:Male; D018408:Patch-Clamp Techniques; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D015398:Signal Transduction; D013373:Substance P / Q000502:physiology*
chemical_list: D011963:Receptors, GABA-A; D013373:Substance P; D051744:Protein Kinase C-epsilon