VOLTAGE-GATED CALCIUM CHANNELS IN MIGRAINE PATHOPHYSIOLOGY

偏头痛病理生理学中的电压门控钙通道

• 批准号: 8759402
• 负责人: YUQING CAO
• 金额: $ 33.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759402
• 关键词: Afferent Neurons; Attenuated; Behavior; Binding; Calcium Channel; Caliber; Classic Migraine; Coupled; Coupling; Disease; Dura Mater; Exhibits; Exposure to; Face; Familial Hemiplegic Migraine; Family; Functional disorder; Genes; Goals; Grant; Head; Headache; Healthcare Systems; Homeostasis; Human; Imaging Techniques; Incidence; Individual; Inflammation Mediators; Ion Channel; Ions; Isolectin; Lead; Migraine; Modeling; Monitor; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Neurons; Neurotransmitters; Nociception; Orofacial Pain; Outcome; P-Q type voltage-dependent calcium channel; PHluorin; Paper; Patients; Pharmaceutical Preparations; Population; Potassium Channel; Prevention; Preventive; Public Health; Relative (related person); Research; Signal Transduction; Skin; Societies; Specificity; Spinal Ganglia; Structure of trigeminal ganglion; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic; Trigeminal System; Wild Type Mouse; Work; channel blockers; insight; interdisciplinary approach; loss of function; loss of function mutation; mouse model; mutant; neuronal excitability; neurotransmission; optical imaging; presynaptic; prevent; prophylactic; public health relevance; response; small hairpin RNA; triptans; voltage

DESCRIPTION (provided by applicant): Migraine is one of the most common neurovascular disorders. It is highly debilitating and difficult to treat. The disease mechanisms may involve abnormal ion homeostasis and neurotransmission. Multiple mutations in the gene encoding CaV2.1, the pore-forming subunit of human P/Q-type voltage-gated Ca2+ channel (VGCC), have been associated with familial hemiplegic migraine type 1 (FHM-1), a subclass of migraine with aura. Many of the migraine preventive and abortive drugs modulate the function of VGCCs but with poor specificity and efficacy. The overall goal of this project is to better understand th contribution of individual VGCC subtypes to the pathophysiology of migraine headache. In addition, the potential of VGCC blockers as anti-migraine therapeutics will be directly tested. Recent studies from our lab have found that loss-of-function (LOF) CaV2.1 mutations cause a decrease of P/Q- type current and a compensatory increase in N-type VGCC current in all subtypes of trigeminal ganglion (TG) and dorsal root ganglion neurons. Interestingly, a selective increase in LVA T-type VGCC current occurs only in small-diameter TG neurons that do not bind to isolectin B4 (IB4-). Moreover, LOF CaV2.1 mutations results in hyper-excitability of small IB4- neurons innervating the dura but not the facial skin. This is consistent with the fact that, other than migraine headache, FHM-1 patients do not show higher incidence of other somatic or orofacial pain. Importantly, pretreatment of wild-type mice with T- or N-type VGCC blockers significantly reduced the duration of head-directed nocifensive behavior in a mouse model of headache, indicating that VGCCs are involved in the activation of the neuronal circuit underlying migraine headache. In this project we propose to employ a multidisciplinary approach to investigate the mechanisms through which multiple VGCCs regulate the excitability and synaptic transmission of dural afferent neurons, thereby modulating the gain of the migraine circuit. First, we will test the hypothesis that P/Q-type Ca2+ channels regulate the excitability o small IB4- dural afferent neurons via functional coupling of the Ca2+-activated TRESK background K+ channels. We will investigate whether enhancing TRESK channel activity can reverse the hyper-excitability of dural afferent neurons and inhibit headache-like behavior in a mouse model. Secondly, we will use optical imaging technique to elucidate the contribution of N-type and other subtypes of VGCCs to Ca2+ influx synaptic transmission at dural afferent terminals. Finally, we will use a mouse model of headache to test the hypothesis that N- and T-type VGCCs in dural afferent neurons are potential targets for anti-migraine therapeutics. We will test whether N- and T-type blockers can be used for both abortive and preventive therapy of migraine headache. Taken together, the outcome of this project will offer new insights into the contribution of VGCCs to migraine pathophysiology as well as the therapeutic potential of trigeminal VGCCs and their downstream effector(s) in migraine treatment and prevention.

描述（由申请人提供）：偏头痛是最常见的神经血管疾病之一。它使人极度虚弱且难以治疗。疾病机制可能涉及离子稳态和神经传递异常。 CaV2.1（人类 P/Q 型电压门控 Ca2+ 通道 (VGCC) 的成孔亚基）编码基因的多个突变与家族性偏瘫型偏头痛 1 型 (FHM-1)（先兆偏头痛的一个亚类）相关。许多偏头痛预防和堕胎药物可调节 VGCC 功能，但特异性和疗效较差。该项目的总体目标是更好地了解各个 VGCC 亚型对偏头痛病理生理学的贡献。此外，VGCC 阻滞剂作为抗偏头痛疗法的潜力将得到直接测试。我们实验室最近的研究发现，功能丧失（LOF）CaV2.1突变导致三叉神经节（TG）和背根神经节神经元所有亚型中P/Q型电流减少和N型VGCC电流代偿性增加。有趣的是，LVA T 型 VGCC 电流的选择性增加仅发生在不与异凝集素 B4 (IB4-) 结合的小直径 TG 神经元中。此外，LOF CaV2.1 突变导致支配硬脑膜而非面部皮肤的小 IB4- 神经元过度兴奋。这与以下事实相一致：除了偏头痛之外，FHM-1患者没有表现出更高的其他躯体或口面部疼痛的发生率。重要的是，用 T 型或 N 型 VGCC 阻滞剂预处理野生型小鼠，显着缩短了头痛小鼠模型中头部定向伤害行为的持续时间，表明 VGCC 参与了偏头痛背后的神经元回路的激活。在这个项目中，我们建议采用多学科方法来研究多个 VGCC 调节硬脑膜传入神经元的兴奋性和突触传递的机制，从而调节偏头痛回路的增益。首先，我们将测试以下假设：P/Q 型 Ca2+ 通道通过 Ca2+ 激活的 TRESK 背景 K+ 通道的功能耦合来调节小 IB4- 硬脑膜传入神经元的兴奋性。我们将研究增强 TRESK 通道活性是否可以逆转硬脑膜传入神经元的过度兴奋并抑制小鼠模型中的头痛样行为。其次，我们将利用光学成像技术阐明N型和其他亚型VGCC对硬脑膜传入末梢Ca2+流入突触传递的贡献。最后，我们将使用小鼠头痛模型来检验硬脑膜传入神经元中的 N 型和 T 型 VGCC 是抗偏头痛治疗的潜在靶点的假设。我们将测试 N 型和 T 型阻滞剂是否可用于偏头痛的流产性和预防性治疗。总而言之，该项目的成果将为 VGCC 对偏头痛病理生理学的贡献以及三叉神经 VGCC 及其下游效应器在偏头痛治疗和预防中的治疗潜力提供新的见解。