The serotonin receptor 7 promotes neurite outgrowth via ERK and Cdk5 signaling pathways

Neuropharmacology. 2013 Apr:67:155-67. doi: 10.1016/j.neuropharm.2012.10.026. Epub 2012 Nov 16.

Abstract

Serotonergic neurotransmission is mediated by at least 14 subtypes of 5-HT receptors. Among these, the CNS serotonin receptor 7 (5-HTR7) is involved in diverse physiological processes. Here we show that treatment of murine striatal and cortical neuronal cultures with 5-HTR7 agonists (8-OH-DPAT and LP-211) significantly enhances neurite outgrowth. This effect is abolished by the selective 5-HTR7 antagonist SB-269970, by the ERK inhibitor U0126, by the cyclin-dependent kinase 5 (Cdk5) inhibitor roscovitine, as well as by cycloheximide, an inhibitor of protein synthesis. These data indicate that 5-HTR7 activation stimulates extensive neurite elongation in CNS primary cultures, subserved by ERK and Cdk5 activation, and de novo protein synthesis. Two-dimensional (2D) gel electrophoresis coupled to Western blot analyses reveals both qualitative and quantitative expression changes in selected cytoskeletal proteins, following treatment of striatal primary cultures with LP-211. In particular, the 34 kDa isoform of MAP1B is selectively expressed in stimulated cultures, consistent with a role of this protein in tubulin polymerization and neurite elongation. In summary, our results show that agonist-dependent activation of the endogenous 5-HTR7 in CNS neuronal primary cultures stimulates ERK- and Cdk5-dependent neurite outgrowth, sustained by modifications of cytoskeletal proteins. These data support the hypothesis that the 5-HTR7 might play a crucial role in shaping neuronal morphology and behaviorally relevant neuronal networks, paving the way to new approaches able to modulate CNS connectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butadienes / pharmacology
  • Cells, Cultured
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 5 / physiology*
  • Female
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Inbred C57BL
  • Nerve Net / drug effects
  • Nerve Net / metabolism
  • Neurites / drug effects
  • Neurites / physiology*
  • Nitriles / pharmacology
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*

Substances

  • Butadienes
  • Nitriles
  • Receptors, Serotonin
  • U 0126
  • serotonin 7 receptor
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, rat