Crosstalk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons

Kisspeptin 神经元中雌激素和代谢激素信号传导之间的串扰

• 批准号: 10246663
• 负责人: Martin Jeffrey Kelly
• 金额: $ 26.18万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246663
• 关键词: Address; Adult; Agonist; Animals; Appetite Stimulants; Attenuated; Biophysics; Brown Fat; Cations; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Cues; Development; Down-Regulation; Dynorphins; Eating; Electrophysiology (science); Energy Metabolism; Estradiol; Estrogen Receptors; Estrogens; Female; Fertility; Frequencies; GNRH1 gene; Glutamate Receptor; Glutamates; Goals; Gonadal Steroid Hormones; Health; Homeostasis; Hormonal; Hypothalamic structure; Insulin; KISS1 gene; Lead; Leptin; Link; Maintenance; Measures; Medial Dorsal Nucleus; Mediating; Membrane; Messenger RNA; Metabolic; Metabolic hormone; Metabolic syndrome; Metabotropic Glutamate Receptors; Molecular; Molecular Biology; Molecular Genetics; Neurokinin B; Neurons; Neuropeptides; Neurotransmitters; Obesity; Peptides; Physiology; Pro-Opiomelanocortin; Property; Regulation; Reproduction; Research; Role; Signal Pathway; Signal Transduction; Structure of dorsomedial hypothalamic nucleus; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic Transmission; Temperature; Whole-Cell Recordings; estrogenic; hormonal signals; interdisciplinary approach; knock-down; mRNA Expression; neuronal circuitry; neuronal excitability; neuropeptide Y; neurophysiology; novel therapeutics; optogenetics; paraventricular nucleus; parvocellular; programs; receptor; reduced food intake; reproductive success; tool; transmission process; vesicular glutamate transporter 2

Project Summary The long range goals of our research program has been to elucidate the mechanism(s) by which metabolic states and 17β-estradiol (E2) regulate arcuate nucleus kisspeptin (Kiss1ARH) neuronal circuits that are critical for coordinating energy homeostasis and reproduction in females. It is well known that E2 is anorexigenic, and that Kiss1 neurons, which are directly regulated by E2, are essential for pubertal development and adult reproductive success. However, their role in the control of other homeostatic functions is just emerging. Earlier, we found that Kiss1ARH neurons are depolarized/excited by leptin and insulin via canonical transient receptor potential (TRPC) 5 channel signaling and proposed that they may serve as an important hub in the control of energy homeostasis. Recently, we found that high frequency optogenetic stimulation of Kiss1ARH neurons releases glutamate to excite the anorexigenic proopiomelanocortin (POMC) neurons but inhibit the orexigenic neuropeptide Y/agouti-related peptide (AgRP) neurons. E2 increases vesicular glutamate transporter 2 (Vglut2) mRNA expression and glutamate release from female Kiss1ARH neurons to augment the POMC excitation and AgRP inhibition. Also, Kiss1ARH neurons project to and excite AVPV/PeN Kiss1 neurons via glutamate, which drives the GnRH and LH surges. Thus, Kiss1ARH neurons appear to integrate metabolic hormone and gonadal steroid signaling to regulate both energy homeostasis and reproduction via multiple neurotransmitters. Key excitatory cationic channels are upregulated by E2 leading to increased excitability and glutamatergic synaptic transmission, whereas peptide expression and transmission are attenuated by the classical estrogen receptor (ER) signaling pathways. Recently, we have found that the selective membrane estrogen receptor (GqmER) agonist STX increases the excitability of Kiss1ARH neurons without downregulating the peptide expression. Therefore, we hypothesize that estrogenic signaling in Kiss1ARH neurons is important for increasing Kiss1ARH neuronal excitability and maintenance of homeostatic functions critical for reproductive success. Our multidisciplinary approach incorporates a powerful set of cellular, molecular, genetic and optogenetic tools, and our combined expertise in molecular biology, electrophysiology, and whole animal physiology to address the following aims: (1) to measure the estrogenic-mediated increase in excitability of Kiss1ARH neurons using GCaMP6 and Voltron recordings; (2) to elucidate the estrogenic modulation of the synaptic input from Kiss1ARH to hypothalamic paraventricular nucleus neurons using optogenetic stimulation and its effects on food intake; and (3) to elucidate the estrogenic modulation of synaptic input from Kiss1ARH neurons to hypothalamic dorsomedial nucleus neurons and its effects on energy expenditure. Elucidating the circuits and signaling cascades underlying the actions of E2 and the selective GqmER agonist STX will provide a neurophysiological/neuropharmacological framework for a more thorough understanding of the cellular mechanisms by which Kiss1ARH neurons coordinate homeostatic functions with reproduction.

项目摘要 我们研究计划的远距离目标是阐明代谢的机制 状态和17β-雌二醇（E2）调节弓形核核肽（Kiss1arh）神经元电路，这是关键的 用于女性的协调能量体内稳态和繁殖。众所周知，E2是厌食症，并且 那个由E2直接调节的Kiss1神经元对于青春期的发展和成人至关重要 生殖成功。但是，它们在控制其他稳态功能中的作用只是出现。 早些时候，我们发现KISS1ARH神经元被瘦素和胰岛素通过规范瞬态部署/激发 接收器电位（TRPC）5通道信号传导，并提出它们可以用作重要的集线器 控制能量稳态。最近，我们发现Kiss1arh的高频光遗传学模拟 神经元释放谷氨酸以激发厌食症的肌蛋白酶素（POMC）神经元，但抑制 甲状腺素神经肽Y/Agouti相关肽（AGRP）神经元。 E2增加囊泡谷氨酸 转运蛋白2（VGLUT2）mRNA表达和谷氨酸从雌性Kiss1arh神经元释放以增强 POMC兴奋和AGRP抑制作用。此外，Kiss1arh神经元对AVPV/PEN KISS1神经元进行了计划 通过谷氨酸，驱动GNRH和LH涌现。那就是Kiss1arh神经元似乎整合了代谢 马酮和性腺类固醇信号传导通过多个调节能量体内稳态和繁殖 神经递质。 E2更新了关键的兴奋性阳离子渠道，导致令人兴奋的增加和 谷氨酸能突触传播，而果皮表达和传播则被 经典雌激素受体（ER）信号通路。最近，我们发现选择性膜 雌激素受体（GQMER）激动剂STX增加了Kiss1arh神经元的兴奋而无需下调 胡椒表达。因此，我们假设Kiss1arh神经元中的雌激素信号传导很重要 为了增加Kiss1arh神经元的激动和维持稳态功能，对生殖至关重要 成功。我们的多学科方法结合了一组强大的细胞，分子，遗传和 光遗传学工具以及我们在分子生物学，电生理学和全动物方面的综合专业知识 解决以下目的的生理学：（1）测量雌激素介导的兴奋的增加 使用GCAMP6和Voltron录音的Kiss1arh神经元； （2）阐明 使用光遗传学刺激 及其对食物摄入的影响； （3）阐明来自Kiss1arh突触输入的雌激素调制 下丘脑背核神经元及其对能量消耗的影响。阐明 电路和信号级联E2的作用和选择性GQMER AMONIST STX将提供 一种神经生理/神经药物框架，可对细胞有更全面的了解 Kiss1arh神经元协调稳态功能与繁殖的机制。

项目成果

17Beta-estradiol regulation of T-type calcium channels in gonadotropin-releasing hormone neurons.

• DOI: 10.1523/jneurosci.2962-09.2009
• 发表时间: 2009-08-26
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Zhang C;Bosch MA;Rick EA;Kelly MJ;Rønnekleiv OK
• 通讯作者: Rønnekleiv OK

Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis.

• DOI: 10.1159/000338669
• 发表时间: 2013
• 期刊: Neuroendocrinology
• 影响因子: 4.1
• 作者: Washburn N;Borgquist A;Wang K;Jeffery GS;Kelly MJ;Wagner EJ
• 通讯作者: Wagner EJ

Kisspeptin activation of TRPC4 channels in female GnRH neurons requires PIP2 depletion and cSrc kinase activation.

Kisspeptin 激活女性 GnRH 神经元中的 TRPC4 通道需要 PIP2 耗竭和 cSrc 激酶激活。

• DOI: 10.1210/en.2013-1180
• 发表时间: 2013
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Zhang,Chunguang;Bosch,MarthaA;Rønnekleiv,OlineK;Kelly,MartinJ
• 通讯作者: Kelly,MartinJ

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

• DOI: 10.1523/jneurosci.1395-11.2011
• 发表时间: 2011-08-17
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Roepke TA;Qiu J;Smith AW;Rønnekleiv OK;Kelly MJ
• 通讯作者: Kelly MJ

Membrane and nuclear initiated estrogenic regulation of homeostasis.

膜和核启动体内平衡的雌激素调节。

• DOI: 10.1016/j.steroids.2019.108428
• 发表时间: 2021
• 期刊: Steroids
• 影响因子: 2.7
• 作者: Stincic,ToddL;Rønnekleiv,OlineK;Kelly,MartinJ
• 通讯作者: Kelly,MartinJ