Voltage-gated calcium channels as target for anesthetics

我们在药理学中面临的剩余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) 和活动(固定)以及痛感丧失(止痛)和对事件的回忆 (失忆)。据认为，GAS通过神经细胞膜上的多种特异性蛋白发挥作用，并 不同的配基门控和电压门控离子通道受到了广泛的关注。其中之一 麻醉机制中电压门控钙通道(VGCC)研究的重要原因 作用是这些通道在调节突触传递和兴奋性方面是必不可少的。 神经元睡眠通路(如丘脑)和参与学习/记忆的大脑区域(如河马)。 坎普·阿尔地层)。重要的是，我们之前的研究已经确定了低电压激活亚型 VGCC或T-型钙通道(T-通道)的不同种类的气体可抑制 临床相关浓度范围。在过去的二十年里，我们的工作确立了 T型VGCC系列用于急慢性疼痛处理，包括手术后疼痛。然而， VGCCs在GA诱导的催眠和健忘机制中的作用仍不清楚。此外， 尽管在过去的二十年里，我们在理解 气体如何在分子水平上起作用，人们对气体如何引起催眠和记忆知之甚少 在完整的神经元网络水平上的缺陷。因此，这项建议旨在阐明 丘脑皮质(研究区1)和河马T通道的特殊亚型对麻醉效应的影响 CampAl电路(研究领域2)。我们将利用老鼠的遗传学，选择性地击倒 不同的T通道亚型体外和体内电生理学、光学记录以及电池 行为测试来应对这些关键挑战。我们提议的工作有可能推翻前- 列出关于麻醉机制的教条，并将重点转移到被低估的目标上，例如 神经元T通道。我们假设，对GAS作用的神经生理机制的理解 可以将目标T通道用作开发新的和潜在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声明的目标，因为 在NIGMS感兴趣的研究领域内寻求新途径的灵活性。稳定的工作效率 我们实验室的能力和我们在麻醉药理学领域与其他人合作的能力强烈表明 我们的方法将是卓有成效的。这项拟议工作具有创新性，因为它是临床上有用的新机制 将描述全身麻醉剂的效果，如意识丧失和健忘症。它是医学的- 具有重要意义，因为它描述了靶向电压门控钙通道的药物的重要性 以期在临床麻醉中开发更安全的实践。

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.