title: Type-7 metabotropic glutamate receptors negatively regulate α1-adrenergic receptor signalling.
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 Giprotein 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.
authors: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors: Luisa
authors: L
authors: Iacovelli
authors: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors: Luisa
authors: L
authors: Di Menna
authors: Faculty of Biology & Preclinical Medicine, Laboratory of Molecular & Cellular Neurobiology, University of Regensburg, Regensburg, Germany.
authors: Daniel
authors: D
authors: Peterlik
authors: Faculty of Biology & Preclinical Medicine, Laboratory of Molecular & Cellular Neurobiology, University of Regensburg, Regensburg, Germany.
authors: Christina
authors: C
authors: Stangl
authors: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors: Rosamaria
authors: R
authors: Orlando
authors: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors: Gemma
authors: G
authors: Molinaro
authors: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors: Antonio
authors: A
authors: De Blasi
authors: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors: Valeria
authors: V
authors: Bruno
authors: I.R.C.C.S. Neuromed, Pozzilli, Italy.
authors: Giuseppe
authors: G
authors: Battaglia
authors: Faculty of Biology & Preclinical Medicine, Laboratory of Molecular & Cellular Neurobiology, University of Regensburg, Regensburg, Germany.
authors: Peter J
authors: PJ
authors: Flor
authors: Faculty of Biology & Preclinical Medicine, Laboratory of Molecular & Cellular Neurobiology, University of Regensburg, Regensburg, Germany.
authors: Nicole
authors: N
authors: Uschold-Schmidt
authors: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; I.R.C.C.S. Neuromed, Pozzilli, Italy. Electronic address: ferdinandonicoletti@hotmail.com.
authors: Ferdinando
authors: F
authors: Nicoletti
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D018690:Excitatory Amino Acid Agonists; D018340:Receptors, Adrenergic, alpha-1; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7
keywords: Cross-talk; G proteins; Stress; mGlu7 receptors; α(1)-adrenergic receptor