title: The serotonin receptor 7 promotes neurite outgrowth via ERK and Cdk5 signaling pathways.
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.
authors.affiliation: Department of Biological Sciences, University of Naples Federico II, Section of Physiology, Via Mezzocannone 8, 80134 Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Speranza
authors.forename: A
authors.initials: A
authors.lastname: Chambery
authors.forename: M
authors.initials: M
authors.lastname: Di Domenico
authors.forename: M
authors.initials: M
authors.lastname: Crispino
authors.forename: V
authors.initials: V
authors.lastname: Severino
authors.forename: F
authors.initials: F
authors.lastname: Volpicelli
authors.forename: M
authors.initials: M
authors.lastname: Leopoldo
authors.forename: G C
authors.initials: GC
authors.lastname: Bellenchi
authors.forename: U
authors.initials: U
authors.lastname: di Porzio
authors.forename: C
authors.initials: C
authors.lastname: Perrone-Capano
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D002070:Butadienes; D009570:Nitriles; D011985:Receptors, Serotonin; C113580:U 0126; C104425:serotonin 7 receptor; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat