Melatonin inhibits voltage-gated potassium K V 4.2 channels and negatively regulates melatonin secretion in rat pineal glands.

Melatonin is synthesized in and secreted from the pineal glands, and regulates circadian rhythms. Although melatonin has been reported to modulate the activity of ion channels in several tissues, its effects on pineal ion channels remain unclear. In the present study, the effects of melatonin on voltage-gated K ⁺ (K _V ) channels, which play a role in regulating the resting membrane potential, were examined in rat pinealocytes. The application of melatonin reduced pineal K _V currents in a concentration-dependent manner (IC ₅₀ =309 mM). An expression analysis revealed that K _V 4.2 channels were highly expressed in rat pineal glands. Melatonin-sensitive currents were abolished by the small interfering RNA knockdown of K _V 4.2 channels in rat pinealocytes. In human embryonic kidney 293 (HEK293) cells expressing K _V 4.2 channels, melatonin decreased outward currents (IC ₅₀ =479 mM). Inhibitory effects were mediated by a shift in voltage dependence from steady-state inactivation to a hyperpolarizing direction. This inhibition was observed even in the presence of 100 nM luzindole, an antagonist of melatonin receptors. Melatonin also blocked the activity of K _V 4.3, K _V 1.1, and K _V 1.5 channels in reconstituted HEK293 cells. The application of 1 mM melatonin caused membrane depolarization in rat pinealocytes. Furthermore, K _V 4.2 channel inhibition by 5 mM 4-aminopyridine attenuated melatonin secretion induced by 1 mM noradrenaline in rat pineal glands. These results strongly suggest that melatonin directly inhibited K _V 4.2 channels and caused membrane depolarization in pinealocytes, resulting in a decrease in melatonin secretion through parasympathetic signaling pathway. This mechanism may function as a negative-feedback mechanism of melatonin secretion in pineal glands.