Beta-arrestins (β-arrs) are initially known as negative regulators of
G protein-coupled receptors (GPCRs). Recently, there is increasing evidence suggesting that β-arrs also serve as scaffolds and adapters that mediate distinct intracellular signal transduction initiated by GPCR activation. In the previous study, we have shown that
metabotropic glutamate receptor 7 (
mGluR7) and
extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling may be involved in the developmental
sevoflurane neurotoxicity. In the present study, we showed that activation of
mGluR7 with a group III mGluRs orthosteric agonist LAP4 or an atypical
mGluR7 allosteric agonist N,N'-bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride (
AMN082) significantly attenuated
sevoflurane-induced neuronal apoptosis. Interestingly, this neuroprotective role of LAP4 could be partially reduced by β-arr1
small interfering RNA (
siRNA) or β-arr2
siRNA transfection. In contrast, β-arr2
siRNA transfection alone abolished the effects of
AMN082 on
sevoflurane neurotoxicity. In addition, administration of LAP4 or
AMN082 significantly enhanced Phospho-ERK1/2 in
sevoflurane neurotoxicity, which could be abrogated by β-arr2
siRNA transfection, but not by β-arr1
siRNA transfection. Increased β-arr2-dependent Phospho-ERK1/2 signaling alleviated
sevoflurane neurotoxicity by inhibiting bad phosphorylation. We also found that the neuroprotective role of
AMN082 was completely reversed by ERK1/2 inhibitor 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]
butadiene (
U0126). Alternatively, treatment with
U0126 partially suppressed the neuroprotective of LAP4, suggesting that other mechanisms may be implicated in this process. Further investigation indicated that, in the scenario of
sevoflurane neurotoxicity, application of LAP4 (but not
AMN082) increased the interaction of β-arrs with transcriptional factors
CREB binding protein (CBP) and p300. LAP4 also enhanced the β-arr1-dependent H3 and H4 acetylation in
sevoflurane neurotoxicity. For the behavior study, treatment with LAP4 or
AMN082 significantly improved the emotional and spatial learning and
memory disorders induced by postnatal
sevoflurane exposure. These results suggested that β-arr1 and 2 may differently modulate
mGluR7 signaling in developmental
sevoflurane neurotoxicity. This study also reveals a β-arr-biased agonism at GPCRs (e.g.
mGluR7).