Voltage-gated calcium channels as target for anesthetics

电压门控钙通道作为麻醉靶点

• 批准号: 10402374
• 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/10402374
• 关键词: Absence of pain sensation; Acute Pain; Address; Amnesia; Anesthesia procedures; Anesthetics; Area; Brain region; Calcium; Calcium Channel; Categories; Clinical; Development; Drug Targeting; Electrophysiology (science); Event; Face; Family; General anesthetic drugs; Goals; Hippocampal Formation; Hippocampus (Brain); 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.

我们在药理学中所面临的一个基本挑战是如何破解