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

Cell Signal. 2016 Aug;28(8):979-88. doi: 10.1016/j.cellsig.2016.05.004. Epub 2016 May 6.


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.

Keywords: 5-HT(1D) receptor; A-type K(+) currents (I(A)); Neuronal excitability; Trigeminal ganglion (TG) neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Ion Channel Gating / drug effects
  • MAP Kinase Signaling System / drug effects
  • Membrane Potentials / drug effects
  • Mice, Inbred ICR
  • Models, Biological
  • Neurons / drug effects
  • Neurons / metabolism*
  • Potassium Channels / metabolism*
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT1D / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Sumatriptan / pharmacology
  • Trigeminal Ganglion / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Potassium Channels
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT1D
  • Serotonin 5-HT1 Receptor Agonists
  • Sumatriptan
  • Proto-Oncogene Proteins B-raf
  • Cyclic AMP-Dependent Protein Kinases
  • p38 Mitogen-Activated Protein Kinases