Heterocomplex formation of 5-HT_2A-mGlu₂ and its relevance for cellular signaling cascades

详细信息	查看全文 | 推荐本文 |

• 作者：Hannah K. Delille^a ; Judith M. Becker^a ; Sabrina Burkhardt^a ; Barbara Bleher^a ; Georg C. Terstappen^a ; Martin Schmidt^a ; Axel H. Meyer^a ; Liliane Unger^a ; Gerard J. Marek^b ; Mario Mezler^a ; ^{mario.mezler@abbott.com}
• 关键词：mGlu2 ; 5-HT2A ; Heterocomplex ; GPCR crosstalk
• 刊名：Neuropharmacology
• 出版年：2012
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：June, 2012
• 卷：62
• 期：7
• 页码：2184-2191
• 文件大小：651 K

摘要

Dopamine, serotonin and glutamate play a role in the pathophysiology of schizophrenia. In the brain a functional crosstalk between the serotonin receptor 5-HT_2A and the metabotropic glutamate receptor mGlu₂ has been demonstrated. Such a crosstalk may be mediated indirectly through neuronal networks or directly by receptor oligomerization. A direct link of the 5-HT_2A-mGlu₂ heterocomplex formation to receptor function, i.e. to intracellular signaling, has not been fully demonstrated yet. Here we confirm the formation of 5-HT_2A-mGlu₂ heterocomplexes using quantitative Snap/Clip-tag based HTRF methods. Additionally, mGlu₂ formed complexes with 5-HT_2B and mGlu₅ but not 5-HT_2C indicating that complex formation is not specific to the 5-HT_2A-mGlu₂ pair. We studied the functional consequences of the 5-HT_2A-mGlu₂ heterocomplex addressing cellular signaling pathways. Co-expression of receptors in HEK-293 cells had no relevant effects on signaling mediated by the individual receptors when mGlu₂ agonists, antagonists and PAMs, or 5-HT_2A hallucinogenic and non-hallucinogenic agonists and antagonists were used. Hallucinogenic 5-HT_2A agonists induced signaling through G_q/11, but not G_i and thus did not lead to modulation of intracellular cAMP levels. In membranes of the medial prefrontal cortex [³H]-LY341495 binding competition of mGlu_2/3 agonist LY354740 was not influenced by 2,5-dimethoxy-4-iodoamphetamine (DOI). Taken together, the formation of GPCR heterocomplexes does not necessarily translate into second messenger effects. These results do not put into question the well-documented functional cross-talk of the two receptors in the brain, but do challenge the biological relevance of the 5-HT_2A-mGlu₂ heterocomplex.