Voltage-gated calcium channels as target for anesthetics

电压门控钙通道作为麻醉靶点

• 批准号: 10620169
• 负责人: Slobodan M. Todorovic
• 金额: $ 48.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620169
• 关键词: Absence of pain sensation; Acute Pain; Address; Amnesia; Anesthesia procedures; Anesthetics; Area; Brain region; Calcium; Calcium Channel; Calcium Channel Inhibition; Categories; Clinical; Collaborations; Collection; Development; Drug Targeting; Electrophysiology (science); Event; Face; Family; General anesthetic drugs; Goals; Hippocampal Formation; Hippocampus; Hypnosis; Immobilization; Ion Channel Gating; Learning; Ligands; Medical; Membrane; Memory; Memory impairment; Molecular; Movement; National Institute of General Medical Sciences; Neurons; Optics; Pathway interactions; Pharmacology; Postoperative Pain; Productivity; Protein Isoforms; Proteins; Regulation; Research; Role; Sleep; Synaptic Transmission; T-Type Calcium Channels; Thalamic structure; Unconscious State; Work; behavior test; chronic pain; clinical effect; clinically relevant; flexibility; in vivo; innovation; interest; knock-down; mouse genetics; neurophysiology; novel; pain processing; pain sensation; voltage

One of the remaining fundamental challenges we face in pharmacology is deciphering the mechanisms of action of general anesthetics (GAs). A complete anesthetic state involves loss of consciousness (hypnosis) and movement (immobilization), as well as loss of pain sensation (analgesia) and recollection of the event (amnesia). It is believed that GAs act through the multiple but specific proteins on neuronal membrane and different ligand-gated and voltage-gated ion channels have received a significant consideration. One of the compelling reasons to study voltage-gated calcium channels (VGCCs) in the mechanisms of anesthetic actions is that these channels are essential in regulation of synaptic transmission and excitability in the neuronal sleep pathway (e.g. thalamus) and in the brain regions involved in learning/memory (e.g. hippo- campal formation). Importantly, our previous studies have established that low-voltage-activated subtype of VGCCs or T-type calcium channels (T-channels) are inhibited by different classes of GAs within the clinically relevant concentration range. For the past two decades our work has established the role of the family of T-type VGCCs in acute and chronic pain processing, including post-surgical pain. However the role of VGCCs in the mechanisms of GA-induced hypnosis and amnesia remains elusive. Furthermore, despite substantial progress that has been made in the last two decades towards our understanding of how GAs act at the molecular level, much less is known about how GAs cause hypnosis and memory deficit at the level of intact neuronal networks. Hence, this proposal aims to elucidate the contribution of specific subtypes of T-channels to anesthetic effects in the thalamocortical (Research area 1) and hippo- campal circuitry (Research area 2). We will take advantage of mouse genetics, selective knock-down of different T-channel isoforms ex vivo and in vivo electrophysiology, optical recordings, as well as a battery of behavioral tests to address these key challenges. Our proposed work has the potential to overturn ex- isting dogma about anesthetic mechanisms and to shift the focus to underappreciated targets, such as neuronal T-channels. We posit that understanding the neurophysiological mechanisms of action of GAs that target T-channels may be used as a starting point to develop novel and potentially safer approaches and practices in clinical anesthesia. MIRA mechanism is well suited to achieve our stated goals because of flexibility to pursue new avenues within the research area of interest to NIGMS. Consistent productivity of our lab and our ability to collaborate with others in the field of anesthetic pharmacology strongly suggest that our approach will be fruitful. The proposed work is innovative in that new mechanisms of useful clinical effects of general anesthetics such as loss of consciousness and amnesia will be characterized. It is med- ically significant because it describes the importance of drugs that target voltage-gated calcium channels for potential development of safer practices in clinical anesthesia.

我们在药理学中面临的剩余基本挑战之一是破译其机制 全身麻醉药 (GA) 的作用。完全麻醉状态会导致意识丧失（催眠） 和运动（固定），以及痛觉丧失（镇痛）和事件回忆 （健忘症）。据信 GA 通过神经元膜上的多种但特定的蛋白质起作用 不同的配体门控和电压门控离子通道已受到重要考虑。之一 研究麻醉机制中电压门控钙通道 (VGCC) 的令人信服的理由 作用在于这些通道对于调节突触传递和兴奋性至关重要 神经元睡眠通路（例如丘脑）和参与学习/记忆的大脑区域（例如河马） 营的形成）。重要的是，我们之前的研究已经确定低电压激活亚型 VGCC 或 T 型钙通道 (T 通道) 受到不同类别 GA 的抑制 临床相关的浓度范围。在过去的二十年里，我们的工作确立了 T 型 VGCC 家族在急性和慢性疼痛处理（包括术后疼痛）中的作用。然而 VGCCs 在 GA 诱导的催眠和遗忘机制中的作用仍然难以捉摸。此外， 尽管过去二十年来我们在理解 GA如何在分子水平发挥作用，人们对GA如何引起催眠和记忆知之甚少 完整神经元网络水平的缺陷。因此，该提案旨在阐明 T 通道的特定亚型对丘脑皮质（研究领域 1）和河马的麻醉作用 坎帕尔电路（研究领域 2）。我们将利用小鼠遗传学，选择性敲低 不同的 T 通道亚型离体和体内电生理学、光学记录以及电池 的行为测试来解决这些关键挑战。我们提出的工作有可能推翻前 树立关于麻醉机制的教条，并将焦点转移到未被充分认识的目标上，例如 神经元 T 通道。我们假设了解 GA 作用的神经生理学机制 目标 T 通道可作为开发新颖且可能更安全的方法的起点 以及临床麻醉实践。 MIRA 机制非常适合实现我们既定的目标，因为 在 NIGMS 感兴趣的研究领域内寻求新途径的灵活性。稳定的生产力 我们实验室的能力以及我们在麻醉药理学领域与其他人合作的能力强烈表明 我们的方法将会富有成果。拟议的工作具有创新性，因为有用的临床新机制 将描述全身麻醉的影响，例如意识丧失和健忘症。它是医学- 具有重要意义，因为它描述了针对电压门控钙通道的药物的重要性 促进临床麻醉中更安全实践的潜在发展。