Regulatory Effect of General Anesthetics on Activity of Potassium Channels

Neurosci. Bull. https://doi.org/10.1007/s12264-018-0239-1 www.neurosci.cn www.springer.com/12264 REVIEW Regulatory Effect of General Anesthetics on Activity of Potassium Channels Yan Li1,2 • Jie Xu1,2 • Yun Xu1,2 • Xiao-Yun Zhao1,2 • Ye Liu1,2 • Jie Wang1,2 • Guang-Ming Wang1,2 • Yan-Tian Lv1,2 • Qiong-Yao Tang1,2 • Zhe Zhang1,2 Received: 30 November 2017 / Accepted: 12 April 2018 Ó The Author(s) 2018 Abstract General anesthesia is an unconscious state induced by anesthetics for surgery. The molecular targets and cellular mechanisms of general anesthetics in the mammalian nervous system have been investigated during past decades. In recent years, K? channels have been identified as important targets of both volatile and intravenous anesthetics. This review covers achievements that have been made both on the regulatory effect of general anesthetics on the activity of K? channels and their underlying mechanisms. Advances in research on the modulation of K? channels by general anesthetics are summarized and categorized according to four large K? channel families based on their amino-acid sequence homology. In addition, research achievements on the roles of K? channels in general anesthesia in vivo, especially with regard to studies using mice with K? channel knockout, are particularly emphasized. Keywords General anesthesia
Potassium channel
Ion channel Yan Li, Jie Xu, Yun Xu and Xiao-Yun Zhao contributed equally to this review. & Zhe Zhang 1 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China 2 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou 221004, China Introduction Since the early 19th century, general anesthetics have been used to induce a state of unconsciousness for surgery. Modern anesthesiology defines a complete general anesthetic effect as including unconsciousness, amnesia, analgesia, and muscle relaxation that is indispensable for modern surgery. Hitherto, myriad molecular targets of general anesthetics have been identified, such as gammaaminobutyric acid receptor, the N-methyl-D-aspartate receptor families, and ion channels [1–6]. Among the many kinds of ion channels, potassium (K?) channels are the most diverse and ubiquitous, playing important roles in controlling neuronal excitability and neurotransmitter release in the central nervous system by determining the membrane potential of neurons [7–12]. Thus, many studies have been conducted on the regulatory effects of general anesthetics on K? channel activity. Also, data on these effects have accumulated, and this review summarizes recent research achievements in this area, especially emphasizing studies using K? channel knockout (KO) mice. K? channels that have been studied as general anesthetic targets have been assigned to 4 categories according to a standard nomenclature by The International Union of Basic and Clinical Pharmacology (IUPHAR) and the Human Genome Organisation Gene Nomenclature Committee (HGNC) [7]. They are voltage-gated (Kv) channels, the background/leak or tandem 2-pore (K2P) families, inwardly-rectifying (Kir) channels, and Ca2?activated (KCa) channels. Research advances related to the effects of general anesthetics on these channels are summarized based on the above classification. 123 Neurosci. Bull. Modulation of Kv Channels by General Anesthetics The opening of Kv channels is regulated by a membrane potential change and triggered by moving of the voltage sensor domain located on the S4 segment. The voltagegated Kv channel family includes 40 genes encoding poreforming subunits that are divided into 12 subfamilies (Kv1–Kv12) based on sequence homology (Fig. 1A–C). The HGNC and IUPHAR nomenclature and names based on the homologous channels in Drosophila are shown in Fig. 1A [13]. Members of the Shaker-Related K1 Channel Family (Kv1.1–Kv1.6) are Important Targets of Volatile Anesthetics The Shaker channel was the first cloned voltage-dependent K? channel from Drosophila [14, 15]. Flies with a mutated Shaker gene shake their legs under ether anesthesia (hence the name). Subsequently, Shaker-related K? channels were cloned from mammals and named the Kv1.x channel family. Given the critical role Kv channels play in limiting neuronal excitability, studies of the effects of general anesthetics on the Shaker channel began almost immediately after it was cloned. The earliest study performed on Xenopus oocytes revealed that chloroform and halothane reduce the macroscopic conductance of the Shaker channel while isoflurane increases its macroscopic conductance [16]. Consistent with these results, subsequent studies on Drosophila showed that halothane alters the electroretinogram by reducing its transient component at light-off via inactivation of the Shaker channel [17]. Meanwhile, the sleep state, which differs from anesthesia but shares some of its characteristics, is also shorter in Drosophila with a mutated Shaker channel [18]. These results suggested that Shaker-related K? channels are important targets of volatile anesthetics (Table 1). Since then, the effects of general anesthetics on Shakerrelated K? channels in mammals have been widely studied. Barber et al. reported that 1 mmol/L sevoflurane potentiates Drosophila Shaker B, Kv1.2, and Kv1.5 channel currents over the physiological range of membrane potential (-60 to -40 mV) [19]. These results were further confirmed and expanded by a subsequent study by Lioudyno et al., who reported that a sub-surgical dose of sevoflurane (0.2 mmol/L) potentiates the currents of Kv1.1, Kv1.2, Kv1.3, and Kv1.5 channels at low depolarizing potentials (-40 to 0 mV) in a heterologous expression system. But at higher depolarization potentials (30 to 60 mV), the currents of Kv1.1 and Kv1.2 channels are still 123 Fig. 1 Phylogenetic trees of the Kv channel family and critical c structure of Kv1.2 channel for sevoflurane binding. A Amino acid sequences of Kv1–9 channels were aligned by MEGA software with the Clustal W method and analyzed by the neighbor joining test. B, C Kv7 subfamily and Kv 10–12 subfamilies are shown separately because of the low amino acid sequence similarity with other Kv channels. Names of channel subtypes are labeled in color based on their different responses to volatile anesthetics in experiments performed in vitro with patch clamp. The channels that can be activated by volatile anesthetics are shown in red; channels inhibited by volatile anesthetics are shown in yellow; and channels insensitive to volatile anesthetics are shown in green. Channels with unknown responses to volatile anesthetics are in black color. The protein IDs of Kv channels used in this sequence alignment are as follows: Kv1.1 (NP_000208), Kv1.2 (NP_004965), Kv1.3 (NP_002223), Kv1.4 (NP_002224), Kv1.5 (NP_002225), Kv1.6 (NP_002226), Kv1.7 (NP_114092), Kv1.8 (NP_005540); Kv2.1 (NP_004966), Kv2.2 (NP_004761), Kv3.1 (NP_004967), Kv3 (...truncated)