Cannabinoid Inhibition of Divalent Metal Transporter-1 Activity

描述（由申请人提供）：？9-tetrahydrocannabinol (?9-THC)是大麻植物大麻的主要精神活性成分，它通过与中枢神经系统大麻素受体CB1和外周受体CB2相互作用介导许多行为和药理作用。内源性大麻素也激活这些g蛋白偶联受体，负向调节腺苷酸环化酶活性，正向调节向内纠偏K+通道。据报道，大麻素的受体非依赖性作用也对许多离子通道产生负调控，包括t型Ca2+通道、TASK-1通道和Na+通道。在最近对含有已知生物活性分子的小分子文库的筛选中，人们发现？9-THC还能有效阻断二价金属转运蛋白-1 （DMT1）对铁的吸收。DMT1负责通过肠道吸收膳食铁，并在受体介导的血清铁结合蛋白转铁蛋白摄取后将铁传递到外周组织。这个完全出乎意料和新颖的发现提出了铁代谢和大麻素作用之间关系的直接和深刻的问题。为了开发新的见解来解释大麻素如何干扰DMT1的铁运输，并确定这种活动所带来的生理后果，拟议的项目将：1)检查由慢性？9-THC管理;2)探索G蛋白通过CB受体相互作用对DMT1活性的偶联调控；3)研究大麻素与DMT1的结合以及这种相互作用可能引发的转运体磷酸化状态的变化。公共卫生相关性：该项目将确定大麻素如何干扰二价金属转运蛋白-1对铁的摄取。人们对确定大麻素作用靶点非常感兴趣，因为改变内源性大麻素活性的药物正在被开发用于控制肥胖（利莫那班），预防骨质疏松（HU-308）和治疗多发性硬化症（Sativex），目前用于艾滋病和癌症患者（Marinol）。

DESCRIPTION (provided by applicant): ?9-tetrahydrocannabinol (?9-THC) is the major psychoactive component of the marijuana plant Cannabis sativa, and it produces a number of behavioral and pharmacological effects mediated through interactions with the central nervous system cannabinoid receptor CB1 and the peripheral receptor CB2. Endogenous cannabinoids also activate these G-protein coupled receptors to negatively regulate adenylate cyclase activity and positively regulate inward rectifying K+ channels. Receptor-independent effects of cannabinoids have also been reported to negatively regulate a number of ion channels, including T-type Ca2+ channels, TASK-1 channels, and Na+ channels. In a recent screen of small molecule libraries containing known bioactive molecules, it was discovered that ?9-THC also potently blocks iron uptake by Divalent Metal Transporter-1 (DMT1). DMT1 is responsible for dietary iron absorption across the intestine as well as the delivery of iron to peripheral tissues after receptor-mediated uptake of the serum iron-binding protein transferrin. This completely unexpected and novel finding raises immediate and profound questions about the relationships between iron metabolism and cannabinoid action. To develop new insights to explain how cannabinoids perturb iron transport by DMT1 and to determine what physiological consequences ensue from this activity, the proposed project will: 1) Examine changes in the iron status of weanling rats resulting from chronic ?9-THC administration; 2) Explore G protein-coupled regulation of DMT1 activity through CB receptor interactions; and 3) Study binding of cannabinoids to DMT1 and changes in the phosphorylation state of the transporter that may be elicited through such interactions. PUBLIC HEALTH RELEVANCE: This project will determine how cannabinoids interfere with iron uptake by Divalent Metal Transporter-1. There is significant interest in identifying targets of cannabinoid action since drugs that modify endogenous cannabinoid activity are being developed to control obesity (Rimonabant), to prevent osteoporosis (HU-308) and to treat multiple sclerosis (Sativex), and are in current use for AIDS and cancer patients (Marinol).