Inhibition of delta-1 glutamate receptor current by extracellular protons

Decreases in brain pH are associated with numerous neurological and neuropsychiatric conditions yet the molecular mechanisms linking decreased brain pH with these disorders are incomplete. The ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission in the brain and are inhibited by extracellular protons; however, the proton sensitivity of the delta-glutamate receptor subclass of iGluRs is unknown. Using whole-cell patch-clamp recordings of serotonin neurons in mouse brain slices and activating alpha 1-adrenergic receptors to induce delta 1 glutamate receptor (GluD1_R) current, we demonstrated that GluD1_R current is inhibited by physiological drops in extracellular pH. Unlike other iGluRs, protons inhibited GluD1_R current via a voltage-independent decrease in unitary current. Moreover, mice lacking GluD1_R showed impaired behavioral responses to inhalation of CO₂. Taken together, this study continues to expand on the growing body of evidence positing GluD1_R as functional ion channels and suggests that GluD1_R facilitate pH sensing in vivo.