Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades.

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Citation

Delille HK, Becker JM, Burkhardt S, Bleher B, Terstappen GC, Schmidt M, Meyer AH, Unger L, Marek GJ, Mezler M

Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades.

Neuropharmacology. 2012 Jun;62(7):2184-91. doi: 10.1016/j.neuropharm.2012.01.010. Epub 2012 Jan 25.

PubMed ID
22300836 [ View in PubMed
]
Abstract

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 mGlu(2) 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)-mGlu(2) 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)-mGlu(2) heterocomplexes using quantitative Snap/Clip-tag based HTRF methods. Additionally, mGlu(2) formed complexes with 5-HT(2B) and mGlu(5) but not 5-HT(2C) indicating that complex formation is not specific to the 5-HT(2A)-mGlu(2) pair. We studied the functional consequences of the 5-HT(2A)-mGlu(2) 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 mGlu(2) 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 [(3)H]-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)-mGlu(2) heterocomplex.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
5-hydroxytryptamine receptor 2AP28223Details
Metabotropic glutamate receptor 2Q14416Details