The clinical features of long QT syndrome result from episodic life-threatening cardiac arrhythmias, specifically the polymorphic ventricular tachycardia torsades de pointes. KVLQT1 has been established as the human chromosome 11-linked gene responsible for more than 50% of inherited long QT syndrome. Here we describe the cloning of a full-length KVLQT1 cDNA and its functional expression. KVLQT1 encodes a 676-amino acid polypeptide with structural characteristics similar to voltage-gated potassium channels. Expression of KvLQT1 in Xenopus oocytes and in human embryonic kidney cells elicits a rapidly activating, K ؉ -selective outward current. The I Kr -specific blockers, E-4031 and dofetilide, do not inhibit KvLQT1, whereas clofilium, a class III antiarrhythmic agent with the propensity to induce torsades de pointes, substantially inhibits the current. Elevation of cAMP levels in oocytes nearly doubles the amplitude of KvLQT1 currents. Coexpression of minK with KvLQT1 results in a conductance with pharmacological and biophysical properties more similar to I Ks than other known delayed rectifier K ؉ currents in the heart.

Benign familial neonatal convulsions (BFNC), a class of idiopathic generalized epilepsy, is an autosomal dominantly inherited disorder of newborns. BFNC has been linked to mutations in two putative K ؉ channel genes, KCNQ2 and KCNQ3. Amino acid sequence comparison reveals that both genes share strong homology to Kv-LQT1, the potassium channel encoded by KCNQ1, which is responsible for over 50% of inherited long QT syndrome. Here we describe the cloning, functional expression, and characterization of K ؉ channels encoded by KCNQ2 and KCNQ3 cDNAs. Individually, expression of KCNQ2 or KCNQ3 in Xenopus oocytes elicits voltagegated, rapidly activating K ؉ -selective currents similar to KCNQ1. However, unlike KCNQ1, KCNQ2 and KCNQ3 currents are not augmented by coexpression with the KCNQ1 ␤ subunit, KCNE1 (minK, IsK). Northern blot analyses reveal that KCNQ2 and KCNQ3 exhibit similar expression patterns in different regions within the brain. Interestingly, coexpression of KCNQ2 and KCNQ3 results in a substantial synergistic increase in current amplitude. Coexpression of KCNE1 with the two channels strongly suppressed current amplitude and slowed kinetics of activation. The pharmacological and biophysical properties of the K ؉ currents observed in the coinjected oocytes differ somewhat from those observed after injecting either KCNQ2 or KCNQ3 by itself. The functional interaction between KCNQ2 and KCNQ3 provides a framework for understanding how mutations in either channel can cause a form of idiopathic generalized epilepsy.Potassium channels are the largest and most diverse group of ion channels. They are primary regulators of resting membrane potential and action potential configuration and, therefore, modulate excitability of neurons, cardiac myocytes, and other electrically active cells. Recent identification of KCNQ1 (KvLQT1), the gene responsible for more than 50% of inherited cardiac long QT syndrome (LQTS), 1 established a new family of six-transmembrane domain K ϩ channels (1). KCNQ1, in combination with the KCNE1 subunit, encodes the slow component of the cardiac delayed rectifier K ϩ current (2-4), and mutations in KCNQ1, which occur in LQTS patients, partially or completely inhibit the channel in a dominant-negative fashion (5, 6). In an attempt to identify additional members of the KCNQ1 K ϩ channel gene family, the KCNQ1 sequence was used to search DNA and protein sequence data banks. Two additional KCNQ1-related genes, KCNQ2 and KCNQ3, were identified.Recent publications indicate that mutations in KCNQ2 or KCNQ3 are associated with BFNC, an autosomal dominantly inherited epilepsy in newborns (7-9). Preliminary functional characterization of KCNQ2 confirmed that this gene encodes a voltage-activated K ϩ channel (9). Here we describe the cloning, tissue distribution, and functional expression of both KCNQ2 and KCNQ3. More importantly, we demonstrate that these two channels interact functionally with each other and with KCNE1. EXPERIMENTAL PROCEDURES Molecular Cloning and Expression of KCNQ2 and KCNQ3-5ЈRap...

In LQTS-affected individuals these mutations would be predicted to result in a diminution of the cardiac I(Ks) current, subsequent prolongation of cardiac repolarization, and an increased risk of arrhythmias.

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The potassium channel activators cromakalim and pinacidil were recently shown to have anti-ischemic properties in isolated globally ischemic rat hearts. The effects of two reported blockers of ATP-sensitive potassium channels, glibenclamide (glyburide) and sodium 5-hydroxydecanoate, on the anti-ischemic efficacy of cromakalim were determined in this model. Buffer-perfused rat hearts were subjected to 25 minutes of ischemia followed by 30 minutes of reperfusion. Pretreatment of these hearts with 60 ,uM cromakalim significantly decreased indexes of contractile function but caused a significant improvement of postreperfusion function and a significant decrease in release of lactate dehydroxygenase and in end-diastolic pressure. Pretreatment with glibenclamide at concentrations that reversed the preischemic effects of cromakalim (0.05 and 1.0 ,M) also significantly reversed its postischemic protective effects. Sodium 5-hydroxydecanoate (100 and 300 ,uM) had no effect on the preischemic (negative inotropic) effects of cromakalim but completely reversed its cardioprotective effects. Sodium 5-hydroxydecanoate did not reverse the cardioprotective effects of the calcium entry blocker diltiazem. In phenylephrine-contracted rat aorta, glibenclamide (0.1-10 pM) inhibited cromakalim-induced relaxation, whereas sodium 5-hydroxydecanoate (10-1,000 JAM) had no effect. Similarly, the ability of cromakalim to shorten cardiac action potential duration in guinea pig papillary muscle and to increase outward whole-cell potassium currents in isolated myocytes was inhibited by glibenclamide, whereas sodium 5-hydroxydecanoate was without effect. Thus, both glibenclamide and sodium 5-hydroxydecanoate inhibited the effects of cromakalim after reperfusion; however, sodium 5 -hydroxydecanoate, unlike glibenclamide, had no effect in nonischemic preparations. These results suggest that sodium 5-hydroxydecanoate is an ischemia-selective inhibitor of ATP-sensitive potassium channels. (Circulation Research 1991;69:949-958 channel mechanism was implicated for the antiischemic effects of these compounds, since their protective actions were reversed by glibenclamide. Recently, sodium 5 -hydroxydecanoate (5 -HD, Figure 1), a proposed class III antiarrhythmic agent, which is structurally unrelated to glibenclamide, has been shown to inhibit cardiac ATP-sensitive potassium channels.10"11 A previous study12 indicated that 5-HD completely reversed the postischemic cardioprotective effects of cromakalim, yet 5-HD did not inhibit the preischemic coronary dilator effects of cromakalim. Glibenclamide completely inhibited both the preischemic coronary dilator effect and the postischemic cardioprotective effects of cromakalim. These preliminary observations led us to believe that 5-HD may possess some degree of ischemia selectivity. The use of coronary flow as an indicator of preischemic activity is imperfect, however, because the negative inotropic effects of cromakalim would complicate the interpretation of the coronary flow data. Therefore, to investigate...