Delta-1 glutamate receptors (GluD1 R ) are members of the ionotropic glutamate receptor family. The channel of GluD1 R does not open in response to glutamate and the identity of an orthosteric agonist is unknown. However, using whole-cell electrophysiological recordings from serotonin neurons in acute mouse brain slices, we have demonstrated that synaptic activation of α-1 adrenergic receptors (α1-A R ) produces a slow, excitatory postsynaptic current that is carried by GluD1 R channels (α1-A R -GluD1 R current). We also found that GluD1 R are open at a low-level and carry a reproducible “tonic” current under our basal recording conditions. Our discovery of α1-A R -GluD1 R and tonic GluD1 R currents provides a novel tool to investigate possible allosteric regulators on GluD1 R channels. It is well-established that NMDA receptors have an extracellular proton binding site that, when bound, inhibits NMDA R current. Here, we show that GluD1 R are also inhibited by extracellular protons. We used a bicarbonate-based Krebs’ buffer extracellular solution and adjusted the pH from 7.4 to 6.8 by increasing the concentration of carbon dioxide from 5% to 20%. Extracellular pH of 6.8 reversibly reduced α1-A R -GluD1 R current by 60%. To determine whether extracellular pH 6.8 was inhibiting noradrenaline release, we bypassed the presynaptic element and applied exogenous noradrenaline. Application of noradrenaline produced an inward current which was reduced by ∼50% when applied at pH of 6.8, demonstrating that the inhibition of α1-A R -GluD1 R current by extracellular protons was not due to a reduction in noradrenaline release. Analysis of the membrane noise variance indicated a reduction in single channel current by ∼55% in extracellular pH 6.8. Lastly, in extracellular pH of 6.8, tonic GluD1 R current is also reduced by ∼50%. Together, the data indicate that GluD1 R channels are sensitive to protons within the physiologically relevant pH range. Physiological consequences of proton inhibition of GluD1 R will be discussed.
Kain et al. (Sun,) studied this question.