Store-operated calcium channels in neuropathic pain

描述（由申请人提供）：神经性疼痛是对执业医师的临床挑战，也是社会的巨大负担。尽管神经性疼痛的机制仍有待确定，但钙渗透离子通道和受体与疼痛以及与慢性疼痛状态相关的神经可塑性有关。储运钙（SOC）通道是高度Ca2+选择性的阳离子通道，由内质网钙的释放和消耗激活。SOC通道的激活导致许多钙依赖性细胞过程所需的持续高细胞质Ca2+水平。在不可兴奋细胞中，SOC通道由新发现的Orai亚基（Orai1/2/3，孔隙形成亚基）和基质相互作用分子（STIM） 1和STIM2 （ER Ca2+传感器，作为它们的激活剂）组成。在神经系统中，已知SOC通道影响神经递质释放和突触可塑性。STIM2在神经元缺血诱导的胞质Ca2+积累中是必需的，但神经元中SOC通道的基本特性和SOC通道的分子成分尚不清楚。近年来，我们在脊髓背角神经元中发现了SOC通道的功能表达，并证明了SOC通道的激活参与突触传递。这些观察结果对SOC通道的功能和疼痛信号传递中与这些通道激活相耦合的信号通路的性质提出了疑问。我们还发现备用神经损伤（SNI）后不同时间点的SOC通道表达上调。基于这些发现，我们假设SOC通道可能在神经性疼痛中起作用。为了验证我们的假设，我们将结合膜片钳记录、钙成像记录、Taqman实时pcr和行为测试的方法。总的来说，我们的长期目标是确定慢性疼痛的关键分子靶点。本研究的目的是确定背角神经元SOC通道的基本性质，识别编码SOC通道的分子，并确定SOC通道家族在神经性疼痛中的作用。本研究的预期结果是在疼痛通路中发现新的钙信号，并为神经性疼痛的发生和维持提供新的机制。

DESCRIPTION (provided by applicant): Neuropathic pain represents a clinical challenge for the practicing physician and is a great burden to society. Although the mechanisms underlying neuropathic pain remain to be established, calcium-permeable ion channels and receptors have been implicated in pain as well as in the neuroplasticity associated with chronic pain states. Store-operated calcium (SOC) channels are highly Ca2+-selective cation channels that are activated by the release and depletion of calcium from the endoplasmic reticulum. Activation of SOC channels leads to sustained high cytosolic Ca2+ levels that are required for many calcium-dependent cellular processes. SOC channels are composed of newly discovered Orai subunits (Orai1/2/3, pore- forming subunits), and stromal interaction molecules (STIM) 1 and STIM2 (the ER Ca2+ sensors, serve as their activators) in non-excitable cells. In the nervous system, SOC channels are known to influence neurotransmitter release and synaptic plasticity. STIM2 is essential for ischemia-induced cytosolic Ca2+ accumulation in neurons, but the basic properties of SOC channels and molecular components underlying SOC channels in neurons are unexplored. Recently, we found that SOC channels are functionally expressed in spinal dorsal horn neurons and demonstrated that activation of SOC channels is involved in synaptic transmission. These observations raise questions as to the function of SOC channels and to the nature of the signaling pathways that are coupled to the activation of these channels in pain signal transmission. We also found that the expression of the SOC channels is upregulated at different time points after spare nerve injury (SNI). Based on these findings, we hypothesize that the SOC channels may play a role in neuronpathic pain. To test our hypothesis, we will combine the methods of patch-clamp recording, calcium imaging recording, Taqman real-time-PCR and behavioral testing. Overall, our long-term goal is to identify key molecular targets involved in chronic pain. The goals of this proposal are to determine basic properties of SOC channels, to identify molecules encoding SOC channels in dorsal horn neurons, and to determine the role of SOC channel family in neuropathic pain. The expected outcome of this research is the identification of new calcium signaling in pain pathway and a new mechanism underlying the development and maintenance of neuropathic pain.