N-type Calcium Channels in Nociceptive Neurons

伤害感受神经元中的 N 型钙通道

• 批准号: 7271103
• 负责人: Diane Lipscombe
• 金额: $ 37.14万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-02 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271103
• 关键词: type; Calcium; Channels; Nociceptive; Neurons

DESCRIPTION (provided by applicant): In this proposal we study the physiological significance of cell-specific alternative splicing of the voltage-gated N-type calcium channel CaVa1 subunit in nociceptive neurons of the dorsal root ganglia. N- type calcium channels regulate release of glutamate and substance P from primary sensory afferents in the superficial dorsal horn of the spinal cord. The N-type calcium channel is an important target in chronic pain therapy. Inhibition of presynaptic N-type calcium channels is also a therapeutically important site of action of opiates. We recently discovered a unique splice isoform of the N-type calcium channel CaV2.2 subunit, CaV2.2e[37a], that is expressed in many nociceptive neurons. Our recent data show that this unique CaV2.2 splice isoform has unique properties. In this proposal we have two main aims. The first is to understand the physiological significance of alternative splicing of CaV2.2 in regulating the activity of N-type channels in sensory neurons from normal animals. We aim to test the possibility that some of the unique electrical properties and pharmacology of nociceptive neurons originate from cell-specific alternative splicing of CaV2.2 (Aim 1). We will also investigate whether alternative splicing of CaV2.2 is modified following nerve injury using two neuropathic pain models (Aim 2). A change in the pattern of alternative splicing of the N-type channel could have profound effects on the efficacy of synaptic transmission and on the responsiveness of nociceptors to drugs that act by inhibiting the N-type channel. This proposal combines our extensive experience in molecular and electrophysiological studies of calcium channels with that of our collaborator Dr. Carl Saab who has expertise using models of neuropathic pain. We propose that alternative splicing optimizes the behavior and pharmacology of N-type channels in the pain pathway. A defect in alternative splicing following nerve injury could contribute to aberrant pain processing and the de-habilitating symptoms of neuropathic pain.

描述（由申请人提供）：在本提案中，我们研究了背根神经节的伤害感受性神经元的电压门控N型钙通道CAVA1亚基的细胞特异性替代剪接的生理意义。 N型钙通道调节谷氨酸和物质从脊髓浅表背角中的原代感觉传入的物质释放。 N型钙通道是慢性疼痛疗法的重要靶标。抑制突触前N型钙通道也是阿片类药物的治疗作用部位。最近，我们发现了N型钙通道CAV2.2亚基Cav2.2e [37a]的独特剪接同工型，它在许多伤害性神经元中表达。我们最近的数据表明，这种独特的CAV2.2剪接同工型具有独特的属性。在此提案中，我们有两个主要目标。首先是了解CAV2.2在调节正常动物的感觉神经元中N型通道活性中的替代剪接的生理意义。我们旨在测试伤害性神经元的某些独特的电性能和药理学源自CAV2.2的细胞特异性替代剪接（AIM 1）。我们还将研究使用两个神经性疼痛模型在神经损伤后修饰Cav2.2的替代剪接（AIM 2）。 N型通道的替代剪接模式的变化可能会对突触传播的功效以及对通过抑制N型通道起作用的药物的反应性产生深远的影响。该提议结合了我们在钙通道的分子和电生理研究方面的丰富经验与我们的合作者Carl Saab博士的经验，他使用神经性疼痛模型具有专业知识。我们建议替代剪接优化疼痛途径中N型通道的行为和药理。神经损伤后替代剪接的缺陷可能导致神经性疼痛的异常疼痛处理和降低的症状。