Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Department of Physiology, Aichi Medical University, Nagakute, Japan.
Am J Physiol Cell Physiol. 2024 Oct 1;327(4):C1023-C1034. doi: 10.1152/ajpcell.00664.2023. Epub 2024 Aug 19.
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) channels, which play a role in regulating the resting membrane potential, were examined in rat pinealocytes. The application of melatonin reduced pineal K currents in a concentration-dependent manner (IC = 309 µM). An expression analysis revealed that K4.2 channels were highly expressed in rat pineal glands. Melatonin-sensitive currents were abolished by the small interfering RNA knockdown of K4.2 channels in rat pinealocytes. In human embryonic kidney 293 (HEK293) cells expressing K4.2 channels, melatonin decreased outward currents (IC = 479 µM). Inhibitory effects were mediated by a shift in the voltage dependence of steady-state inactivation in 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 K4.3, K1.1, and K1.5 channels in reconstituted HEK293 cells. The application of 1 mM melatonin caused membrane depolarization in rat pinealocytes. Furthermore, K4.2 channel inhibition by 5 mM 4-aminopyridine attenuated melatonin secretion induced by 1 µM noradrenaline in rat pineal glands. These results strongly suggest that melatonin directly inhibited K4.2 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. Melatonin is a hormone that is synthesized in and secreted from the pineal glands, which regulates circadian rhythms. However, the effects of melatonin on pineal ion channels remain unclear. The present study demonstrated that melatonin directly inhibited voltage-gated potassium K4.2 channels, which are highly expressed in rat pinealocytes, and induced membrane depolarization, resulting in a decrease in melatonin secretion. This mechanism may function as a negative-feedback mechanism of melatonin secretion in pineal glands.
褪黑素在松果体中合成并分泌，调节昼夜节律。虽然褪黑素已被报道调节几种组织中的离子通道活性，但它对松果体离子通道的影响尚不清楚。在本研究中，研究了褪黑素对调节静息膜电位的电压门控钾 (K) 通道的作用在大鼠松果体细胞中。褪黑素以浓度依赖性方式减少松果体 K 电流（IC = 309 µM）。表达分析表明，K4.2 通道在大鼠松果体中高度表达。褪黑素敏感电流在大鼠松果体细胞中 K4.2 通道的小干扰 RNA 敲低后被消除。在表达 K4.2 通道的人胚肾 293（HEK293）细胞中，褪黑素减少外向电流（IC = 479 µM）。抑制作用是通过稳态失活的电压依赖性向超极化方向的转变介导的。即使在 100 nM 褪黑素受体拮抗剂 luzindole 的存在下，也观察到这种抑制作用。褪黑素还阻断了重组 HEK293 细胞中 K4.3、K1.1 和 K1.5 通道的活性。在大鼠松果体细胞中应用 1 mM 褪黑素引起膜去极化。此外，5 mM 4-氨基吡啶抑制 K4.2 通道可减轻大鼠松果腺中 1 µM 去甲肾上腺素诱导的褪黑素分泌。这些结果强烈表明，褪黑素直接抑制 K4.2 通道并导致松果体细胞去极化，从而通过副交感神经信号通路减少褪黑素分泌。这种机制可能作为松果体中褪黑素分泌的负反馈机制。褪黑素是一种在松果体中合成并分泌的激素，调节昼夜节律。然而，褪黑素对松果体离子通道的影响尚不清楚。本研究表明，褪黑素直接抑制在大鼠松果体细胞中高度表达的电压门控钾 K4.2 通道，并诱导膜去极化，导致褪黑素分泌减少。这种机制可能作为松果体中褪黑素分泌的负反馈机制。
