Two-Pore Domain Potassium Channels: New Sites of Local Anesthetic Action and Toxicity

Abstract

Potassium (K+) channels form the largest family of ion channels with more than 70 such genes identified in the human genome. They are organized in 3 superfamilies according to their predicted membrane topology: (1) subunits with 6 membrane-spanning segments and 1-pore domain, (2) subunits with 2 membrane-spanning segments and 1-pore domain, and (3) subunits with 4 membrane-spanning segments and 2-pore domains arrayed in a tandem position. The last family has most recently been identified and comprises the so-called 2-pore domain potassium (K2P) channels, believed responsible for background or leak K+ currents. Despite their recent discovery, interest in them is growing rapidly with more than 270 references in the literature reported (www.ipmc.cnrs.fr/~duprat/2p/ref2p.htm#2P, accessed October 30, 2004). K2P channels are widely expressed in the central nervous system and are involved in the control of the resting membrane potential and the firing pattern of excitable cells. This article will therefore review recent findings on actions of local anesthetics with respect to 2P channels. It begins with an overview of the role of background K+ channels in neuronal excitability and nerve conduction and is followed by a description of the K2P channel family including experimental evidence for the contribution of K2P channels to the mechanism of action and toxicity of local anesthetics.

Inhibition of Human Two-Pore Domain K+ Channel TREK1 by Local Anesthetic Lidocaine: Negative Cooperativity and Half-of-Sites Saturation Kinetics

“…Modulation of K ϩ channel function, by local anesthetics, may influence the transmission of sensory impulses by altering the resting membrane potential, repolarization after an action potential, and firing frequency of a neuron (Komai and McDowell, 2001). These studies indicate that the effects of local anesthetics in neural tissue may extend beyond the known direct actions on voltage-gated sodium channels (Kindler and Yost, 2005).…”

“…Moreover, increases in neuronal excitability due to inhibition of K 2P channels may contribute to the cardiotoxic and excitotoxic side effects of local anesthetics (Kindler et al, 2003). Bupivacaine, one of the most potent and toxic local anesthetics clinically used, inhibits the K 2P channels TWIK-related acid-sensitive K ϩ channel 1 and TREK1 at clinically relevant concentrations achieved by intravascular injection (ϳ20 M) (Punke et al, 2003;Kindler and Yost, 2005). Lidocaine, an amide local anesthetic, was found to inhibit K 2P channel TWIK-related acid-sensitive K ϩ channel 2 at clinical doses (Kindler et al, 2003).…”

“…In contrast, central nervous system excitation, leading to seizures, has been partly attributed to local anesthetic action on K 2P channels, especially TREK1 (Kindler and Yost, 2005). Lidocaine has also been known to have inhibitory effects on neurophysiologic responses evoked by A␦ and C fibers in the dorsal root ganglion (Ness, 2000).…”

Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes

“…In light of this, there may be a relationship between the cardiac toxicity of bupivacaine and its use-dependent blockade of Na + channels. But it remains uncertain whether inhibition of VGSCs contributes to the systemic toxic effects of LAs, including the initial CNS excitation and pro-convulsive action [16,17] . In this study, we investigated the pharmacological kinetics of bupivacaine on Na v 1.5 expressed in Xenopus oocytes.…”

Interaction of local anesthetics with the K+channel pore domain

“…2,3 Many tetrameric K + channels are also blocked by hydrophobic organic cations such as alkyl derivatives of tetraethylammonium (TEA + ) and amine derivatives with LA activity. [4][5][6] Block of certain drug-sensitive K + channels may induce or suppress abnormal symptoms of electrical excitability. For example, a form of potentially fatal ventricular fibrillation known as acquired long-QT syndrome is triggered by promiscuous drug block of the human hERG (Kv11.1) cardiac channel that mediates repolarization of the ventricular action potential.…”