α, δ- <i>N</i> -Acetyl-glutamine Suppresses Neutrophilic Airway Inflammation by Activating the G Protein-Coupled Receptor/Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase Phosphatase 1 Pathway

l-Glutamine (Gln) suppresses inflammation via upregulation of mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1; however, high dosages required may cause serious side effects. Here, we developed a glutaminase-resistant less-hydrolyzable Gln derivative, α, δ-<i>N</i>-acetyl-glutamine (α, δ-NAG). Oral administration of α, δ-NAG and Gln to ovalbumin-induced asthma model mice suppressed asthmatic parameters at 0.2 and 2 g/kg body weight, respectively. α, δ-NAG upregulated MKP-1 in an extracellular signal-regulated kinase (ERK) MAPK-dependent manner. MKP-1 siRNA abrogated the beneficial effects of α, δ-NAG. α, δ-NAG transiently increased intracellular calcium ([Ca²⁺]-i), resulting in increased Ras activity. Inhibition of Gαq, a G protein subfamily, abrogated the effects of α, δ-NAG on [Ca²⁺]-i and Ras activity. Inhibition of Gαq, Ca²⁺, and Ras abrogated the α, δ-NAG effects, such as ERK phosphorylation, MKP-1 upregulation, and neutrophilia/Th1 responses, in asthmatic mice. Overall, α, δ-NAG exhibited ∼10,000-fold stronger anti-inflammatory activity than Gln, likely attributable to its upregulation of MKP-1 by activating the G protein-coupled receptor (GPCR)/Gαq/Ca²⁺/Ras/ERK cascade.