title: Serotonin type-1D receptor stimulation of A-type K(+) channel decreases membrane excitability through the protein kinase A- and B-Raf-dependent p38 MAPK pathways in mouse trigeminal ganglion neurons.
abstract: Although recent studies have implicated serotonin 5-HT1B/D receptors in the nociceptive sensitivity of primary afferent neurons, the underlying molecular and cellular mechanisms remain unclear. In this study, we identified a novel functional role of the 5-HT1D receptor subtype in regulating A-type potassium (K(+)) currents (IA) as well as membrane excitability in small trigeminal ganglion (TG) neurons. We found that the selective activation of 5-HT1D, rather than 5-HT1B, receptors reversibly increased IA, while the sustained delayed rectifier K(+) current was unaffected. The 5-HT1D-mediated IA increase was associated with a depolarizing shift in the voltage dependence of inactivation. Blocking G-protein signaling with pertussis toxin or by intracellular application of a selective antibody raised against Gαo or Gβ abolished the 5-HT1D effect on IA. Inhibition of protein kinase A (PKA), but not of phosphatidylinositol 3-kinase or protein kinase C, abolished the 5-HT1D-mediated IA increase. Analysis of phospho-p38 (p-p38) revealed that activation of 5-HT1D, but not 5-HT1B, receptors significantly activated p38, while p-ERK and p-JNK were unaffected. The p38 MAPK inhibitor SB203580, but not its inactive analogue SB202474, and inhibition of B-Raf blocked the 5-HT1D-mediated IA response. Functionally, we observed a significantly decreased action potential firing rate induced by the 5-HT1D receptors; pretreatment with 4-aminopyridine abolished this effect. Taken together, these results suggest that the activation of 5-HT1D receptors selectively enhanced IA via the Gβγ of the Go-protein, PKA, and the sequential B-Raf-dependent p38 MAPK signaling cascade. This 5-HT1D receptor effect may contribute to neuronal hypoexcitability in small TG neurons.
authors.affiliation: Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China.
authors.forename: Xianyang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Geriatrics & Institute of Neuroscience, the Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China; Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China.
authors.forename: Junping
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Ni
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
authors.forename: Yangang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China.
authors.forename: Xinghong
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, PR China; Department of Geriatrics & Institute of Neuroscience, the Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China. Electronic address: taoj@suda.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D015640:Ion Channel Gating / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008813:Mice, Inbred ICR; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D015221:Potassium Channels; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D058825:Serotonin 5-HT1 Receptor Agonists; D018170:Sumatriptan; D048493:Proto-Oncogene Proteins B-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 5-HT(1D) receptor; A-type K(+) currents (I(A)); Neuronal excitability; Trigeminal ganglion (TG) neurons