Anesthetics block neuronal voltage-gated Ca2+ currents

描述（由申请人提供）： 全身麻醉剂产生麻醉的机制尚未完全了解，但它们可能涉及对控制神经细胞兴奋性的多种离子通道的特定作用。神经元高电压激活（HVA）和低电压激活（LVA）或瞬时（T型）Ca 2+通道在控制神经元兴奋性和递质释放中起关键作用，并且涉及疼痛感知、记忆和唤醒控制。为了探讨T型钙电流抑制在麻醉药作用中的潜在作用，我们将在体外研究全身麻醉药对年轻大鼠脑片丘脑网状核（nRT）神经元的影响。我们的初步结果表明，挥发性全身麻醉药（VA）异氟烷和一氧化二氮（N2 O;笑气）缓慢阻断失活的T型钙电流和潜在的动作电位爆发在nRT神经元在临床相关的浓度。这一点很重要，因为丘脑神经元在产生节律振荡中起着核心作用，而节律振荡又控制着意识水平、感觉认知和疼痛通路，以及可能导致癫痫发作的异常兴奋性。因此，这些实验将有助于更好地理解VA对特定亚型的Ca 2+通道的作用对麻醉状态的镇静、遗忘、抗惊厥和镇痛成分的贡献。希望这些研究有助于更好、更安全的临床麻醉和镇痛实践。 申请方建议对初步发现进行后续研究，研究胞体中T电流阻断的麻醉机制，以及切片中完整nRT神经元的树突。此外，将研究nRT神经元中体细胞和树突T通道的分子特性。这些实验将为丘脑切片的功能研究奠定基础，其中T型Ca 2+电流在神经元兴奋性，突触整合和突触传递中的作用将得到解决。VA在破坏丘脑中T型钙电流介导的突触传递和突触整合中的这种潜在作用可能是VA抑制CNS兴奋并有助于全身麻醉临床效果的重要但未被认识的机制的基础。

DESCRIPTION (provided by applicant): The mechanisms by which general anesthetics produce anesthesia are not completely understood but it is likely that they involve specific effects on multiple classes of ion channels that control excitability of nerve cells. Neuronal high voltage-activated (HVA) and low voltage-activated (LVA) or transient (T-type) Ca2+ channels play a key role in control of neuronal excitability and transmitter release, and are implicated in pain perception, memory and control of arousal. To address the potential role of T-type Ca2+ current inhibition in the action of anesthetics, we will examine the effects of general anesthetics in vitro in the neurons of thalamic reticular nucleus (nRT) in slices from young rats. Our preliminary results indicate that the volatile general anesthetics (VA) isoflurane and nitrous oxide (N2O; laughing gas) block slowly inactivating T-type Ca2+ currents and underlying burst of action potentials in nRT neurons in clinically relevant concentrations. This is important since thalamic neurons play a central role in generation of rhythmic oscillations, which in turn control the level of consciousness, sensory cognitive and pain pathways, as well as abnormal excitability that can contribute to seizures. Therefore, these experiments will help in better understanding of the contribution of actions of VAs on specific subtypes of Ca2+ channels to hypnotic-sedative, amnesic, anticonvulsant and analgesic components of anesthetic state. It is hoped that these studies will contribute to better and safer practice of clinical anesthesia and analgesia. The applicant proposes to follow up the initial findings with investigations of the anesthetic mechanisms of blockade of T currents in the somata, as well as dendrites of intact nRT neurons in slices. Additionally, the molecular identity of somatic and dendritic T channels in nRT neurons will be investigated. These experiments will set the stage for functional studies in thalamic slices where the roles of T type Ca2+ current in neuronal excitability, synaptic integration and synaptic transmission will be addressed. This potential role of VAs in disrupting synaptic transmission and synaptic integration mediated by T -type calcium currents in the thalamus, may underlie an important but unappreciated mechanism by which VAs depress excitation in CNS and contribute to the clinical effects of general anesthesia.