The roles of K_ATP channels including Kir6.2 in regulation of emotional behaviors and stress responses

抄録

ATP-sensitive potassium (K_ATP) channels consist of two structurally different subunits: a pore-forming subunit of the Kir6.0-family (Kir6.1 or Kir6.2) and a regulatory sulfonylurea receptor subunit (SUR1, SUR2A or SUR2B). Although Kir6.2 is widely distributed in the brain, the mechanisms that underlie the impact of Kir6.2 on emotional behavior and stress responses are not yet fully understood.

At the first in the present study, to clarify the role of Kir6.2 in emotional behavior, we investigated the behavioral characteristics of Kir6.2-knockout (Kir6.2^-/-) mice. Kir6.2^-/- mice showed impaired general behavior in a locomotor activity test and open field test. In addition, anxiety-like behavior was observed in the open field test, elevated plus-maze test and light-dark test. In particular, excessive anxiety-like behavior was observed in female Kir6.2^-/- mice. Moreover, we investigated whether Kir6.2 is expressed on monoamine neurons in the brain. Immunohistochemical studies showed that Kir6.2 was co-localized with tryptophan hydroxylase (TPH), a marker of serotonergic neurons, in dorsal raphe nuclei. Kir6.2 was also co-localized with tyrosine hydroxylase (TH), a marker of dopaminergic/noradrenergic neurons, in the ventral tegmental area/locus coeruleus. Next, we checked the protein levels of TH and TPH in the midbrain. Interestingly, TPH expression was significantly elevated in female Kir6.2^-/- mice. These results suggest that Kir6.2 in monoamine neurons, especially serotonergic neurons, could play a key role in emotional behavior.

Furthermore, to clarify the role of Kir6.2 in stress responses, we investigated the changes in serum corticosterone levels induced by acute restraint stress in Kir6.2^-/- mice. Under the non-stressed condition, basal corticosterone levels were higher in Kir6.2^-/- mice compared with WT mice. In addition, the increases in serum corticosterone levels induced by exposure to acute restraint stress were also greater in Kir6.2^-/- mice. Interestingly, these phenomena were more prominent in females. Next, we investigated whether Kir6.2 is expressed on GR-positive cells in hippocampal CA1 and DG. Immunohistochemical studies showed that Kir6.2 was co-localized with GR-positive cells in hippocampal CA1 and DG. These results suggest that Kir6.2 in GR-positive cells could play a key role in stress responses via the HPA axis.