In mammalian cardiac cells, a variety of transient or sustained K+ currents contribute to the repolarization of action potentials. There are two main components of the delayed-rectifier sustained K+ current, I(Kr) (rapid) and I(Ks), (slow). I(Kr) is the product of the gene HERG, which is altered in the long-QT syndrome, LQT2. A channel with properties similar to those of the I(Ks) channel is produced when the cardiac protein IsK is expressed in Xenopus oocytes. However, it is a small protein with a very unusual structure for a cation channel. The LQT1 gene is another gene associated with the LQT syndrome, a disorder that causes sudden death from ventricular arrhythmias. Here we report the cloning of the full-length mouse K(V)LQT1 complementary DNA and show that K(V)LQT1 associates with IsK to form the channel underlying the I(Ks) cardiac current, which is a target of class-III anti-arrhythmic drugs and is involved in the LQT1 syndrome.

Volatile anesthetics produce safe, reversible unconsciousness, amnesia and analgesia via hyperpolarization of mammalian neurons. In molluscan pacemaker neurons, they activate an inhibitory synaptic K+ current (IKAn), proposed to be important in general anesthesia. Here we show that TASK and TREK-1, two recently cloned mammalian two-P-domain K+ channels similar to IKAn in biophysical properties, are activated by volatile general anesthetics. Chloroform, diethyl ether, halothane and isoflurane activated TREK-1, whereas only halothane and isoflurane activated TASK. Carboxy (C)-terminal regions were critical for anesthetic activation in both channels. Thus both TREK-1 and TASK are possibly important target sites for these agents.

TREK-1 is a two-pore-domain background potassium channel expressed throughout the central nervous system. It is opened by polyunsaturated fatty acids and lysophospholipids. It is inhibited by neurotransmitters that produce an increase in intracellular cAMP and by those that activate the Gq protein pathway. TREK-1 is also activated by volatile anesthetics and has been suggested to be an important target in the action of these drugs. Using mice with a disrupted TREK-1 gene, we now show that TREK-1 has an important role in neuroprotection against epilepsy and brain and spinal chord ischemia. Trek1−/− mice display an increased sensitivity to ischemia and epilepsy. Neuroprotection by polyunsaturated fatty acids, which is impressive in Trek1+/+ mice, disappears in Trek1−/− mice indicating a central role of TREK-1 in this process. Trek1−/− mice are also resistant to anesthesia by volatile anesthetics. TREK-1 emerges as a potential innovative target for developing new therapeutic agents for neurology and anesthesiology