Voltage-gated calcium channels as target for anesthetics

我们在药理学中面临的剩下的基本挑战之一是破译 全身麻醉药（GAs）的作用。完全麻醉状态包括意识丧失（催眠） 和运动（固定），以及痛觉丧失（镇痛）和对事件的回忆 （健忘症）。据信，GAs通过神经元膜上的多种但特异的蛋白质起作用， 不同的配体门控和电压门控离子通道已经受到了重要的考虑。之一 研究电压门控钙通道（VGCC）在麻醉机制中的重要性 这些通道在调节突触传递和兴奋性中是必不可少的。 神经元睡眠通路（例如丘脑）和参与学习/记忆的脑区域（例如河马- 形成）。重要的是，我们以前的研究已经确定，低电压激活亚型 的VGCC或T型钙通道（T通道）被不同类别的GAs抑制。 临床相关浓度范围。过去二十年来，我们的工作确立了 T型VGCC家族在急性和慢性疼痛处理中的作用，包括手术后疼痛。然而 VGCCs在GA诱导的催眠和遗忘机制中的作用仍然是难以捉摸的。此外，委员会认为， 尽管在过去的二十年里，我们在理解 GA如何在分子水平上发挥作用，但对GA如何引起催眠和记忆的了解要少得多 完整神经元网络水平的缺陷。因此，本建议旨在阐明 T通道的特定亚型对丘脑皮质（研究区域1）和河马的麻醉作用， 电子电路（研究领域2）。我们将利用小鼠遗传学的优势，选择性地敲低 不同的T-通道同种型离体和体内电生理学、光学记录以及电池 来应对这些关键挑战。我们提出的工作有可能推翻前- 关于麻醉机制的教条，并将重点转移到未被重视的目标，如 神经元T通道我们认为，了解GAs的神经生理学作用机制 靶向T通道可以作为开发新的和潜在的更安全的方法的起点， 和临床麻醉实践。MIRA机制非常适合实现我们的既定目标，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 我们的实验室和我们的合作能力与他人在麻醉药理学领域强烈建议 我们的方法会有成效所提出的工作是创新的，新的机制，有用的临床 将描述全身麻醉剂的作用，例如意识丧失和健忘症。它是医学- 因为它描述了靶向电压门控钙通道的药物的重要性 为临床麻醉中更安全实践的潜在发展。

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.