Type-7 metabotropic glutamate receptors negatively regulate α1-adrenergic receptor signalling

Luisa Iacovelli, Luisa Di Menna, Daniel Peterlik, Christina Stangl, Rosamaria Orlando, Gemma Molinaro, Antonio De Blasi, Valeria Bruno, Giuseppe Battaglia, Peter J. Flor, Nicole Uschold-Schmidt, Ferdinando Nicoletti

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

We studied the interaction between mGlu7 and α1-adrenergic receptors in heterologous expression systems, brain slices, and living animals. L-2-Amino-4-phosphonobutanoate (L-AP4), and L-serine-O-phosphate (L-SOP), which activate group III mGlu receptors, restrained the stimulation of polyphosphoinositide (PI) hydrolysis induced by the α1-adrenergic receptor agonist, phenylephrine, in HEK 293 cells co-expressing α1-adrenergic and mGlu7 receptors. The inibitory action of L-AP4 was abrogated by (i) the mGlu7 receptor antagonist, XAP044; (ii) the C-terminal portion of type-2 G protein coupled receptor kinase; and (iii) the MAP kinase inhibitors, UO126 and PD98059. This suggests that the functional interaction between mGlu7 and α1-adrenergic receptors was mediated by the βγ-subunits of the Gi protein and required the activation of the MAP kinase pathway. Remarkably, activation of neither mGlu2 nor mGlu4 receptors reduced α1-adrenergic receptor-mediated PI hydrolysis. In mouse cortical slices, both L-AP4 and L-SOP were able to attenuate norepinephrine- and phenylephrine-stimulated PI hydrolysis at concentrations consistent with the activation of mGlu7 receptors. L-AP4 failed to affect norepinephrine-stimulated PI hydrolysis in cortical slices from mGlu7−/− mice, but retained its inhibitory activity in slices from mGlu4−/− mice. At behavioural level, i.c.v. injection of phenylephrine produced antidepressant-like effects in the forced swim test. The action of phenylephrine was attenuated by L-SOP, which was inactive per se. Finally, both phenylephrine and L-SOP increased corticosterone levels in mice, but the increase was halved when the two drugs were administered in combination. Our data demonstrate that α1-adrenergic and mGlu7 receptors functionally interact and suggest that this interaction might be targeted in the treatment of stress-related disorders.

Original languageEnglish (US)
Pages (from-to)343-353
Number of pages11
JournalNeuropharmacology
Volume113
DOIs
StatePublished - Feb 1 2017

Keywords

  • Cross-talk
  • G proteins
  • Stress
  • mGlu7 receptors
  • α-adrenergic receptor

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Iacovelli, L., Di Menna, L., Peterlik, D., Stangl, C., Orlando, R., Molinaro, G., De Blasi, A., Bruno, V., Battaglia, G., Flor, P. J., Uschold-Schmidt, N., & Nicoletti, F. (2017). Type-7 metabotropic glutamate receptors negatively regulate α1-adrenergic receptor signalling. Neuropharmacology, 113, 343-353. https://doi.org/10.1016/j.neuropharm.2016.10.018