Fasting and 17β-estradiol differentially modulate the M-current in neuropeptide Y neurons

Multiple K⁺ conductances are targets for many peripheral and central signals involved in the control of energy homeostasis. Potential K⁺ channel targets are the KCNQ subunits that form the channels underlying the M-current, a subthreshold, non-inactivating K⁺ current that is a common target for G-protein-coupled receptors. Whole-cell recordings were made from GFP (Renilla)-tagged neuropeptide Y (NPY) neurons from the arcuate nucleus of the hypothalamus using protocols to isolate and characterize the M-current in these orexigenic neurons. We recorded robust K⁺ currents in the voltage range of the M-current, which were inhibited by the selective KCNQ channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) (40 μM), in both intact males and ovariectomized, 17β-estradiol (E2)-treated females. Since NPY neurons are orexigenic and are active during fasting, the M-current was measured in fed and fasted male mice. Fasting attenuated the XE991-sensitive current by threefold, which correlated with decreased expression of the KCNQ2 and KCNQ3 subunits as measured with quantitative real-time PCR. Furthermore, E2 treatment augmented the XE991-sensitive M-current by threefold in ovariectomized (vs oil-treated) female mice. E2 treatment increased the expression of the KCNQ5 subunit in females but not KCNQ2 or KCNQ3 subunits. Fasting in females abrogated the effects of E2 on M-current activity, at least in part, by decreasing KCNQ2 and KCNQ3 expression. In summary, these data suggest that the M-current plays a pivotal role in the modulation of NPY neuronal excitability and may be an important cellular target for neurotransmitter and hormonal signals in the control of energy homeostasis in both males and females.