Substance P suppresses GABAA receptor function via protein kinase C in primary sensory neurones of bullfrogs.
1. The effects of substance P (SP) and related tachykinins on the function of gamma-aminobutyric acid-A (GABAA) receptors were examined in acutely dissociated neurones of bullfrog dorsal root ganglia (DRG) by using whole-cell voltage-clamp techniques. 2. Application of SP (10 nM to 1 microM) depressed inward currents produced by GABAA receptor activation (IGABA). Neurokinin A (NKA) and neurokinin B (NKB) also depressed IGABA; the rank order of agonist potency was SP > NKA > NKB. Spantide ([D-Arg1, D-Trp7,9,Leu11]SP) and L-703,606, NK1 receptor antagonists, blocked the SP-induced depression of IGABA. 3. SP irreversibly depressed IGABA, when neurones were intracellularly dialysed with GTP gamma S. Intracellular application of GDP beta S prevented the SP-induced depression of IGABA. Pertussis toxin (PTX) did not block the inhibitory effect of SP on IGABA. 4. The depression of IGABA produced by SP was inhibited by H-7 and PKC(19-36), protein kinase C (PKC) inhibitors, but not by H-9 and HA-1004, protein kinase A inhibitors. IGABA was suppressed by application of sn-1,2-dioctanoyl glycerol (DOG), a PKC activator. 5. It is concluded that activation of neurokinin-1 (NK1) receptors downregulates the function of the GABAA receptor of primary sensory neurones through a PTX-insensitive G-protein. PKC may be involved in the transduction pathway of the tachykinin-induced inhibition of the GABAA receptor.
Department of Physiology, Kurume University School of Medicine, Japan.
K
K
Yamada
T
T
Akasu
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004594:Electrophysiology; D058787:GABA-A Receptor Antagonists; D019204:GTP-Binding Proteins / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011892:Rana catesbeiana; D018039:Receptors, Tachykinin / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015320:Tachykinins / Q000494:pharmacology
D058787:GABA-A Receptor Antagonists; D018039:Receptors, Tachykinin; D015320:Tachykinins; D013373:Substance P; D011493:Protein Kinase C; D019204:GTP-Binding Proteins