We have isolated KCNQ5, a novel human member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. When expressed in Xenopus oocytes, KCNQ5 generated voltage-dependent, slowly activating K ؉ -selective currents that displayed a marked inward rectification at positive membrane voltages. KCNQ5 currents were insensitive to the K ؉ channel blocker tetraethylammonium but were strongly inhibited by the selective M-current blocker linopirdine. Upon coexpression with the structurally related KCNQ3 channel subunit, current amplitudes increased 4 -5-fold. Compared with homomeric KCNQ5 currents, KCNQ3/KCNQ5 currents also displayed slower activation kinetics and less inward rectification, indicating that KCNQ5 combined with KCNQ3 to form functional heteromeric channel proteins. This functional interaction between KCNQ5 and KCNQ3, a component of the M-channel, suggests that KCNQ5 may contribute to a diversity of heteromeric channels underlying native neuronal M-currents.

Slowly activating I Ks (KCNQ1/MinK) channels were expressed in Xenopous oocytes and their sensitivity to chromanols was compared to homomeric KCNQ1 channels. To elucidate the contribution of the b-subunit MinK on chromanol block, a formerly described chromanol HMR 1556 and its enantiomer S5557 were tested for enantio-speci®city in blocking I Ks and KCNQ1 as shown for the single enantiomers of chromanol 293B. Both enantiomers blocked homomeric KCNQ1 channels to a lesser extent than heteromeric I Ks channels. Furthermore, we expressed both WT and mutant MinK subunits to examine the involvement of particular MinK protein regions in channel block by chromanols. Through a broad variety of MinK deletion and point mutants, we could not identify amino acids or regions where sensitivity was abolished or strikingly diminished (42.5 fold). This could indicate that MinK does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to the principal subunit KCNQ1.

KCNQ1 inactivation bears electrophysiological characteristics different from classical N-and C-type inactivation in Shaker-like potassium channels. However, the molecular site of KCNQ1 inactivation has not yet been determined. KCNQ2 channels do not exert a fast inactivation in contrast to KCNQ1 channels. By expressing functional chimeras between KCNQ1 and KCNQ2 in Xenopus oocytes, we mapped the region of this inactivation to transmembrane domain S5 and the pore loop H5 and finally narrowed down the site to positions Gly 272 and Val 307 in KCNQ1. Exchanging these two amino acids individually with the analogous KCNQ2 residue abolished inactivation. Furthermore, a KCNQ1-like inactivation was introduced into KCNQ2 by mutagenesis in the corresponding region, confirming its relevance for the inactivation process. As KCNQ1 inactivation involves the regions S5 and H5, it exhibits a geography distinct from N-or C-type inactivation. Native cardiac I Ks channels comprising KCNQ1 and accessory MinK subunits do not inactivate because of the functional interaction of KCNQ1 with MinK. Mutations in KCNQ1 can lead to long QT1 syndrome, an inherited form of arrhythmia. The long QT1 mutant KCNQ1(L273F) displays a pronounced KCNQ1 inactivation. Here we show that when expressing mutant I Ks channels formed from KCNQ1(L273F) and MinK, MinK association no longer eliminates KCNQ1 inactivation. This results in smaller repolarizing currents in the heart and therefore represents a novel mechanism leading to long QT syndrome.Ion channels regulate the membrane potential of excitable cells. These are proteins containing aqueous pores and undergo conformational changes leading to the defined gating states "open" and "closed," where open channels are conducting and closed channels are nonconducting. In many channels there are additional "inactivated" states, which are also nonconducting and which follow the open states because of an activating physiological stimulus. Among voltage-gated potassium channels, there are two major types of inactivation. N-type inactivation is mediated by an intracellular "ball," located within the N terminus of either the pore-forming protein or a modulatory ␤-subunit, which plugs the ion channel pore (1-4). In C-type inactivation the outer vestibule of the pore itself undergoes conformational changes (5).Inactivation plays an important physiological role such as determining the sodium spike in neurons and myocytes. Genetic defects, resulting in impaired inactivation of sodium channels, can cause myotonia and a form of long QT syndrome (LQTS) 1 (6, 7). The KCNQ gene family represents a group of recently identified voltage-gated potassium channels, and disease-causing mutations have been identified in 4 of 5 known KCNQ genes (8 -13). KCNQ1 (formerly called KvLQT1), the founding member of this family (8), coassembles with MinK (also called IsK or KCNE1) protein (14) generating slowly activating potassium currents. These constitute the cardiac I Ks conductance, one component of the delayed rectifier repolarizing curre...

L-type calcium current and I(to) are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.

Heteromeric hKv4.3/hKChIP2 currents more closely resemble native epicardial I(to1), suggesting that hKChIP2 is a true beta-subunit of human cardiac I(to1). As a result hKChIP2 might play a role in cardiac diseases, where a contribution of I(to1) has been shown.