Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT1A Serotonin Receptor

被引:18
作者
Bouaziz, Elodie [1 ,2 ,3 ]
Emerit, Michel Boris [1 ,2 ,3 ]
Vodjdani, Guilan [3 ,4 ]
Gautheron, Vanessa [3 ,4 ]
Hamon, Michel [1 ,2 ,3 ]
Darmon, Michele [1 ,2 ,3 ]
Masson, Justine [1 ,2 ,3 ]
机构
[1] INSERM, Ctr Psychiat & Neurosci, U894, F-75014 Paris, France
[2] Univ Paris 05, Sorbonne Paris Cite, F-75270 Paris, France
[3] Univ Paris 06, F-75013 Paris, France
[4] Inst Cerveau & Moelle Epiniere, Ctr Rech, CNRS UMR 7225, INSERM UMR 975, F-75013 Paris, France
关键词
5-HT1A receptor; constitutive and drug-induced internalization; hippocampus; neuron; raphe; recycling; NUCLEUS RAPHE DORSALIS; PLASMA-MEMBRANE; NMDA RECEPTOR; RAB GTPASES; IN-VIVO; PROTEIN; CELLS; TRAFFICKING; BRAIN; AUTORECEPTORS;
D O I
10.1523/JNEUROSCI.0186-13.2014
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Selective serotonin reuptake inhibitors (SSRI) are aimed at increasing brain 5-HT tone; however, this expected effect has a slow onset after starting SSRI treatment because of initial activation of 5-HT1A autoreceptor-mediated negative feedback of 5-HT release. After chronic SSRI treatment, 5-HT1A autoreceptors desensitize, which allows 5-HT tone elevation. Because 5-HT1A receptor (5-HT1AR) internalization has been proposed as a possible mechanism underlying 5-HT1A autoreceptor desensitization, we examined whether this receptor could internalize under well controlled in vitro conditions in the LLC-CPK1 cell line and in raphe or hippocampal neurons from rat embryos. To this goal, cells were transfected with recombinant lentiviral vectors encoding N-terminal tagged 5-HT1AR, and exposed to various pharmacological conditions. Constitutive endocytosis and plasma membrane recycling of tagged-5-HT1AR was observed in LLC-PK1 cells as well as in neurons. Acute exposure (for 1 h) to the full 5-HT1AR agonists, 5-HT and 5-carboxamido-tryptamine, but not the partial agonist 8-OH-DPAT, triggered internalization of tagged 5-HT1AR in serotonergic neurons only. In contrast, sustained exposure (for 24 h) to all agonists induced tagged-5-HT1AR endocytosis in raphe serotonergic neurons and a portion of hippocampal neurons, but not LLC-PK1 cells and partial agonist displayed an effect only in serotonergic neurons. In all cases, agonist-induced tagged 5-HT1AR endocytosis was prevented by the 5-HT1AR antagonist, WAY-100635, which was inactive on its own. These data showed that agonist-induced 5-HT1AR internalization does exist in neurons and depends on agonist efficacy and neuronal phenotype. Its differential occurrence in serotonergic neurons supports the idea that 5-HT1AR internalization might underlie 5-HT1A autoreceptor desensitization under SSRI antidepressant therapy.
引用
收藏
页码:282 / 294
页数:13
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