Abstract
The Na(+)-K(+) pump current (I(p)) and the h-current (I(h)) flowing through hyperpolarization-activated channels (h-channels) participate in generating the resting potential. These two currents are thought to be produced independently. We show here bidirectional interactions between Na(+)-K(+) pumps and h-channels in mesencephalic trigeminal neurons. Activation of I(h) leads to the generation of two types of ouabain-sensitive I(p) with temporal profiles similar to those of instantaneous and slow components of I(h), presumably reflecting Na(+) transients in a restricted cellular space. Moreover, the I(p) activated by instantaneous I(h) can facilitate the subsequent activation of slow I(h). Such counteractive and cooperative interactions were also disclosed by replacing extracellular Na(+) with Li(+), which is permeant through h-channels but does not stimulate the Na(+)-K(+) pump as strongly as Na(+) ions. These observations indicate that the interactions are bidirectional and mediated by Na(+) ions. Also after substitution of extracellular Na(+) with Li(+), the tail I(h) was reduced markedly despite an enhancement of I(h) itself, attributable to a negative shift of the reversal potential for I(h) presumably caused by intracellular accumulation of Li(+) ions. This suggests the presence of a microdomain where the interactions can take place. Thus, the bidirectional interactions between Na(+)-K(+) pumps and h-channels are likely to be mediated by Na(+) microdomain. Consistent with these findings, hyperpolarization-activated and cyclic nucleotide-modulated subunits (HCN1/2) and the Na(+)-K(+) pumpalpha3 isoform were colocalized in plasma membrane of mesencephalic trigeminal neurons having numerous spines.