Inhibition of GluR Current in Microvilli of Sensory Neurons via Na + -Microdomain Coupling Among GluR, HCN Channel, and Na + /K + Pump.

Glutamatergic dendritic EPSPs evoked in cortical pyramidal neurons are depressed by activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels expressed in dendritic spines. This depression has been attributed to shunting effects of HCN current ( I h ) on input resistance or I h deactivation. Primary sensory neurons in the rat mesencephalic trigeminal nucleus (MTN) have the somata covered by spine-like microvilli that express HCN channels. In rat MTN neurons, we demonstrated that I h enhancement apparently diminished the glutamate receptor (GluR) current ( I GluR ) evoked by puff application of glutamate/AMPA and enhanced a transient outward current following I GluR (OT- I GluR ). This suggests that some outward current opposes inward I GluR . The I GluR inhibition displayed a U-shaped voltage-dependence with a minimal inhibition around the resting membrane potential, suggesting that simple shunting effects or deactivation of I h cannot explain the U-shaped voltage-dependence. Confocal imaging of Na+ revealed that GluR activation caused an accumulation of Na+ in the microvilli, which can cause a negative shift of the reversal potential for I h ( E h ). Taken together, it was suggested that I GluR evoked in MTN neurons is opposed by a transient decrease or increase in standing inward or outward I h , respectively, both of which can be caused by negative shifts of E h , as consistent with the U-shaped voltage-dependence of the I GluR inhibition and the OT- I GluR generation. An electron-microscopic immunohistochemical study revealed the colocalization of HCN channels and glutamatergic synapses in microvilli of MTN neurons, which would provide a morphological basis for the functional interaction between HCN and GluR channels. Mathematical modeling eliminated the possibilities of the involvements of I h deactivation and/or shunting effect and supported the negative shift of E h which causes the U-shaped voltage-dependent inhibition of I GluR .