Studies on physiological significance of hyperpolarization-activated cation channels

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to physiological functions such as regulating cell excitability, eliciting rhythmic activities and so on. Four subtypes (HCN1-4) have ever been identified. We previously cloned HCN4, which shows the slowest activation kinetics and the profound modulation by cAMP. To investigate the physiological roles of HCN4, we have generated a transgenic (Tg) mouse, in which tetracycline repressor protein (TetR) is expressed under the control of HCN4 promoter. This mouse was crossbred with another Tg mouse, in which GFP expression is regulated by TetR. Thus, generated Tg mouse expressed GFP in HCN4-expressing cells. We observed on this Tg mouse revealed that GFP fluorescence and HCN4 immunoreactivity (HCN4-IR) were colocalized in the cerebrum, the sino-atrial node, the taste buds and the retina, all of which were previously confirmed to express HCN4. The olfactory receptor neurons (ORN) expressed GFP, where only HCN current (Ih) had been formerly reported, however, its physiological roles remain unknown. HCN4-IR was detected in the olfactory knobs, the soma and the axon bundles of the ORN. We also found that HCN2 was expressed in the axon bundles of the ORN. Electrophysiological studies are in progress to analyze the physiological properties of HCN channels in the ORN.