Steroid Regulation of Ion Channels

离子通道的类固醇调节

• 批准号: 8101225
• 负责人: LESLIE P HENDERSON
• 金额: $ 37.84万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101225
• 关键词: Action Potentials; Acute; Address; Adolescence; Adolescent; Adult; Age; Anabolic steroids; Androgens; Animals; Anterior Hypothalamus; Antineoplastic Agents; Appearance; Athletic; Attention; Body Image; Brain; Cells; Censuses; Child; Chronic; Communities; Competence; Data; Development; Drug usage; Estrus; Exposure to; Female; Female Adolescents; Gonadotropin Hormone Releasing Hormone; Green Fluorescent Proteins; Health; Hormonal; Human; Ion Channel; Kinetics; Knockout Mice; Libido; Medial; Mediating; Mental Health; Methyltestosterone; Mus; Neurons; Neurosecretory Systems; Obesity; Pattern; Periodicity; Phosphorylation; Play; Post-Translational Protein Processing; Preoptic Areas; Process; Prosencephalon; Protein Kinase C; Puberty; Public Health; Recombinants; Regulation; Reproductive Behavior; Reproductive Health; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Rodent; Role; School-Age Population; Self Administration; Steroids; Synapses; Teenagers; Transgenic Mice; Transgenic Organisms; Woman; gamma-Aminobutyric Acid; girls; high school; hypothalamic pituitary gonadal axis; male; malignant breast neoplasm; men; neurosteroids; neurotransmission; patch clamp; prepuberty; programs; receptor; receptor expression; receptor function; reproductive; senescence; sex

DESCRIPTION (provided by applicant): Illicit use of anabolic androgenic steroids (AAS) has become an increasingly prominent health concern. While the spotlight of media attention has been on adult male elite athletes, concern over AAS self-administration in the scientific and public health communities has shifted to the growing use of these steroids by junior high- and high school-age children, especially teenage girls. Many of these adolescent users are not involved in athletics, but are concerned with body image and take the AAS to enhance their physical appearance. The 2000 US Census estimates that 0.5 to 0.8 million teenagers abuse AAS with a mean age for initiation of 15. In humans, early exposure to high levels of androgens alters the onset of puberty, reproductive competence and sexual libido. In rodents, AAS exposure, both prior to puberty and in adults, can produce not only diminished reproductive competence, but also accelerated reproductive senescence. It is particularly relevant to AAS use in adolescence that changes in pubertal onset are associated with increased long-term risks with respect to obesity, breast cancer, drug use and mental health. Moreover, previous studies suggest that long-term risks from AAS abuse are greater in women than in men, that prepubertal and pubertal adolescents are unusually sensitive to the deleterious effects of the AAS, and that many of the AAS effects elicited during adolescence may not be reversible with cessation of drug use. Neurotransmission mediated by gamma-aminobutyric acid type A (GABAA) receptors in forebrain neuroendocrine control regions plays a critical role in regulating both pubertal onset and the expression of normal adult reproductive behaviors. We have shown that chronic AAS treatment alters GABAA receptor expression and function in these regions in an age- and sex-specific manner. We have also shown that acute AAS administration rapidly alters GABAA receptor function via allosteric modulation and that this modulation depends upon subunit composition of the receptor. In the current proposal, we will take advantage of transgenic and knockout mice to determine the role of a and e subunits in AAS-mediated modulation of GABAergic transmission and neuronal activity in gonadotropin releasing hormone (GnRH) neurons that control the hypothalamic-pituitary-gonadal axis. We will also assess how posttranslational modifications of the GABAA receptor regulate allosteric modulation by the AAS and if these changes vary with age, sex and hormonal state of the animal. Our data will generate data important for understanding how these steroids alter neuronal function to produce effects on reproductive health and how their effects differ in men vs. women and adults vs. children who abuse them.

描述（由申请人提供）：非法使用合成代谢雄激素类固醇（AAS）已成为日益突出的健康问题。虽然媒体关注的焦点一直集中在成年男性精英运动员身上，但科学界和公共卫生界对 AAS 自我管理的关注已经转移到初中和高中适龄儿童（尤其是十几岁的女孩）越来越多地使用这些类固醇。这些青少年用户中的许多人不参与体育运动，但关心身体形象并通过 AAS 来增强自己的外表。 2000 年美国人口普查估计，有 0.5 至 80 万青少年滥用 AAS，平均开始年龄为 15 岁。对于人类来说，过早接触高水平的雄激素会改变青春期的开始、生殖能力和性欲。对于啮齿类动物来说，无论是在青春期前还是在成年中，接触 AAS 不仅会导致生殖能力下降，还会加速生殖衰老。与青春期 AAS 的使用尤其相关的是，青春期开始的变化与肥胖、乳腺癌、吸毒和心理健康等长期风险的增加有关。此外，先前的研究表明，女性滥用 AAS 的长期风险比男性更大，青春期前和青春期青少年对 AAS 的有害影响异常敏感，并且青春期期间引起的许多 AAS 影响可能无法通过停止吸毒而逆转。前脑神经内分泌控制区的 A 型 γ-氨基丁酸 (GABAA) 受体介导的神经传递在调节青春期开始和正常成人生殖行为的表达方面发挥着关键作用。我们已经证明，长期 AAS 治疗会以年龄和性别特异性的方式改变这些区域的 GABAA 受体表达和功能。我们还表明，急性 AAS 给药通过变构调节迅速改变 GABAA 受体功能，并且这种调节取决于受体的亚基组成。在当前的提案中，我们将利用转基因和基因敲除小鼠来确定 a 和 e 亚基在 AAS 介导的 GABA 能传递调节和控制下丘脑 - 垂体 - 性腺轴的促性腺激素释放激素 (GnRH) 神经元中的神经元活动中的作用。我们还将评估 GABAA 受体的翻译后修饰如何调节 AAS 的变构调节，以及这些变化是否随动物的年龄、性别和激素状态而变化。我们的数据将产生重要的数据，以了解这些类固醇如何改变神经元功能以对生殖健康产生影响，以及它们对滥用它们的男性与女性、成人与儿童的影响有何不同。

项目成果

Correlating AMPA receptor activation and cleft closure across subunits: crystal structures of the GluR4 ligand-binding domain in complex with full and partial agonists.

关联 AMPA 受体激活和跨亚基裂口闭合：与完全和部分激动剂复合的 GluR4 配体结合结构域的晶体结构。

• DOI: 10.1021/bi8013196
• 发表时间: 2008-12-30
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Gill, Avinash;Birdsey-Benson, Amanda;Jones, Brian L.;Henderson, Leslie P.;Madden, Dean R.
• 通讯作者: Madden, Dean R.

Chronic exposure to anabolic androgenic steroids alters neuronal function in the mammalian forebrain via androgen receptor- and estrogen receptor-mediated mechanisms.

• DOI: 10.1523/jneurosci.3108-09.2009
• 发表时间: 2009-10-07
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Penatti CA;Porter DM;Henderson LP
• 通讯作者: Henderson LP

Sex and exercise interact to alter the expression of anabolic androgenic steroid-induced anxiety-like behaviors in the mouse.

• DOI: 10.1016/j.yhbeh.2014.04.008
• 发表时间: 2014-07
• 期刊: HORMONES AND BEHAVIOR
• 影响因子: 3.5
• 作者: Onakomaiya, Marie M.;Porter, Donna M.;Oberlander, Joseph G.;Henderson, Leslie P.
• 通讯作者: Henderson, Leslie P.

Mad men, women and steroid cocktails: a review of the impact of sex and other factors on anabolic androgenic steroids effects on affective behaviors.

• DOI: 10.1007/s00213-015-4193-6
• 发表时间: 2016-02
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Onakomaiya MM;Henderson LP
• 通讯作者: Henderson LP