Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, Oregon 97239
Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, Oregon 97239.
J Neurosci. 2021 Nov 24;41(47):9688-9701. doi: 10.1523/JNEUROSCI.0622-21.2021. Epub 2021 Oct 15.
Kisspeptin (Kiss1) neurons are essential for reproduction, but their role in the control of energy balance and other homeostatic functions remains unclear. High-frequency firing of hypothalamic arcuate Kiss1 (Kiss1) neurons releases kisspeptin into the median eminence, and neurokinin B (NKB) and dynorphin onto neighboring Kiss1 neurons to generate a slow EPSP mediated by TRPC5 channels that entrains intermittent, synchronous firing of Kiss1 neurons. High-frequency optogenetic stimulation of Kiss1 neurons also releases glutamate to excite the anorexigenic proopiomelanocortin (POMC) neurons and inhibit the orexigenic neuropeptide Y/agouti-related peptide (AgRP) neurons via metabotropic glutamate receptors. At the molecular level, the endoplasmic reticulum (ER) calcium-sensing protein stromal interaction molecule 1 (STIM1) is critically involved in the regulation of neuronal Ca signaling and neuronal excitability through its interaction with plasma membrane (PM) calcium (e.g., TRPC) channels. Therefore, we hypothesized that deletion of in Kiss1 neurons would increase neuronal excitability and their synchronous firing, which ultimately would affect energy homeostasis. Using optogenetics in combination with whole-cell recording and GCaMP6 imaging in slices, we discovered that deletion of in Kiss1 neurons significantly increased the amplitude and duration of the slow EPSP and augmented synchronous [Ca]i oscillations in Kiss1 neurons. Deletion of in Kiss1 neurons amplified the actions of NKB and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting (HFD). Therefore, STIM1 appears to play a critical role in regulating synchronous firing of Kiss1 neurons, which ultimately affects the coordination between energy homeostasis and reproduction. Hypothalamic arcuate kisspeptin (Kiss1) neurons are essential for stimulating the pulsatile release of gonadotropin-releasing hormone (GnRH) and maintaining fertility. However, Kiss1 neurons appear to be a key player in coordinating energy balance with reproduction. The regulation of calcium channels and hence calcium signaling is critically dependent on the endoplasmic reticulum (ER) calcium-sensing protein stromal interaction molecule 1 (STIM1), which interacts with the plasma membrane (PM) calcium channels. We have conditionally deleted in Kiss1 neurons and found that it significantly increased the excitability of Kiss1 neurons and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting (HFD).
Kisspeptin (Kiss1) 神经元对生殖至关重要，但它们在控制能量平衡和其他体内平衡功能中的作用仍不清楚。下丘脑弓状 Kiss1（Kiss1）神经元的高频放电将 kisspeptin 释放到正中隆起中，神经激肽 B（NKB）和强啡肽作用于相邻的 Kiss1 神经元，产生由 TRPC5 通道介导的缓慢 EPSP，使 Kiss1 神经元间歇性、同步放电。高频光遗传学刺激 Kiss1 神经元也会释放谷氨酸，通过代谢型谷氨酸受体兴奋厌食性 proopiomelanocortin (POMC) 神经元并抑制食欲肽神经肽 Y/刺鼠相关肽 (AgRP) 神经元。在分子水平上，内质网 (ER) 钙敏感受体基质相互作用分子 1 (STIM1) 通过与质膜 (PM) 钙 (例如，TRPC) 通道相互作用，在调节神经元钙信号和神经元兴奋性方面起着至关重要的作用。因此，我们假设 Kiss1 神经元中 的缺失会增加神经元的兴奋性和同步放电，最终会影响能量平衡。我们使用光遗传学与全细胞膜片钳记录和 GCaMP6 成像相结合，在切片中发现 Kiss1 神经元中 的缺失显著增加了缓慢 EPSP 的幅度和持续时间，并增强了 Kiss1 神经元中的同步 [Ca]i 振荡。Kiss1 神经元中 的缺失放大了 NKB 的作用，并保护去卵巢雌性小鼠免受高脂肪饮食（HFD）引起的肥胖和葡萄糖不耐受的影响。因此，STIM1 似乎在调节 Kiss1 神经元的同步放电中起着关键作用，这最终会影响能量平衡和生殖之间的协调。下丘脑弓状 kisspeptin (Kiss1) 神经元对于刺激促性腺激素释放激素 (GnRH) 的脉冲释放和维持生育能力至关重要。然而，Kiss1 神经元似乎是协调能量平衡与生殖的关键因素。钙通道的调节，因此钙信号的调节，严重依赖于内质网 (ER) 钙敏感受体基质相互作用分子 1 (STIM1)，它与质膜 (PM) 钙通道相互作用。我们已经条件性地在 Kiss1 神经元中缺失了 ，发现它显著增加了 Kiss1 神经元的兴奋性，并保护去卵巢雌性小鼠免受高脂肪饮食 (HFD) 引起的肥胖和葡萄糖不耐受的影响。
