N-type Calcium Channels in Nociceptive Neurons

描述（由申请人提供）：在本提案中，我们研究了背根神经节痛觉神经元中电压门控n型钙通道CaValpha1亚基的细胞特异性选择性剪接的生理意义。N型钙通道调节脊髓浅背角初级感觉传入神经中谷氨酸和P物质的释放。n型钙通道是慢性疼痛治疗的重要靶点。抑制突触前n型钙通道也是阿片类药物在治疗上的重要作用部位。我们最近发现了一种独特的n型钙通道CaV2.2亚基的剪接异构体，CaV2.2 2e[37a]，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剪接异构体具有独特的性质。在这项建议中，我们有两个主要目的。首先是了解CaV2.2选择性剪接在调节正常动物感觉神经元n型通道活性中的生理意义。我们的目标是测试伤害性神经元的一些独特的电学性质和药理学源于细胞特异性的CaV2.2选择性剪接的可能性（目的1）。我们还将使用两种神经性疼痛模型研究CaV2.2的选择性剪接是否在神经损伤后被修改（目的2）。n型通道选择性剪接模式的改变可能对突触传递的有效性和伤害感受器对通过抑制n型通道起作用的药物的反应性产生深远的影响。该提案结合了我们在钙通道分子和电生理研究方面的丰富经验，以及我们的合作者Carl Saab博士的经验。Carl Saab博士具有使用神经性疼痛模型的专业知识。我们认为选择性剪接优化了疼痛通路中n型通道的行为和药理学。神经损伤后的选择性剪接缺陷可能导致异常的疼痛处理和神经性疼痛的失能症状。

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 CaValpha1 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.