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PubMed1991

Endothelin-induced contractions of rat pulmonary artery are not affected by drugs acting on potassium channels.

The effects of the potassium channel opening drug, pinacidil, and the potassium channel closing drug, tetraethylammonium (TEA), on concentration-response (contraction) curves to spasmogens on rat pulmonary artery were examined. Pinacidil (3 microM) decreased, and TEA (2 mM) increased contractions to 5-hydroxytryptamine (5-HT) more than it did to noradrenaline but contractions to endothelin-1 were only minimally affected. It is concluded that the mechanism whereby endothelin-1 contracts rat pulmonary artery differs from that of noradrenaline or 5-HT in that it does not involve membrane depolarization or calcium entry through voltage operated calcium channels.

Animals↗
PubMed2006

The impact of ancillary subunits on small-molecule interactions with voltage-gated potassium channels.

Voltage-gated potassium channels (Kv channels) are the major determinants of cellular repolarization in excitable cells--they open in response to depolarization and facilitate selective efflux of potassium ions across the plasma membrane. Because of the importance of exquisitely timed cellular repolarization in controlling action potential morphology and duration, Kv channels are attractive therapeutic targets, particularly for drugs aimed at controlling aberrant electrical excitability such as is observed in cardiac arrhythmia and epilepsy. While the pore-forming alpha subunits of Kv channels are sufficient to form functional channels, a host of cytoplasmic and transmembrane ancillary subunits modulate their trafficking, function and regulation in vivo. Here, we consider the impact of ancillary subunits on Kv channel pharmacology, and discuss how increased understanding of the roles of ancillary subunits in native Kv channel complexes will lead to development of safer, more specific and more efficacious therapeutic small molecules.

Animals↗
PubMed2001

Kv2 channels form delayed-rectifier potassium channels in situ.

A non inactivating potassium current known as the delayed rectifier plays a major role in membrane repolarization during an action potential. Whereas several candidate genes exist that code for potassium current, the identities of the molecular isotypes that are responsible in situ for membrane repolarization remain unidentified. We report that Kv2 channels play a major role in action potential repolarization. Kv2 channel elimination resulted in a reduction of the density of noninactivating potassium current and a prolonged impulse duration. In contrast, suppression of noninactivating current carried by Kv1 channels was much less effective in increasing action potential durations. Thus, whereas different potassium channels encode sustained potassium current, their contributions to action potential repolarization vary and require direct examination in situ. Our results indicate that Kv2 subunits function as classic delayed-rectifier channels in vertebrate neurons.

Action Potentials↗
PubMed2001

Location and orientation of minK within the I(Ks) potassium channel complex.

The slowly activating cardiac potassium current (I(Ks)) is generated by a heteromultimeric potassium channel complex consisting of pore-forming (KvLQT1) and accessory (minK) subunits belonging to the KCNQ and KCNE gene families, respectively. Evidence indicating that minK residues line the I(Ks) pore originates from the observation that two minK cysteine mutants (G55C and F54C) render I(Ks) Cd2+-sensitive. We have identified a single cysteine residue in the KvLQT1 S6 segment (Cys-331) that contributes to Cd2+ coordination in conjunction with cysteine residues engineered into the minK transmembrane domain. This observation indicates that minK resides in close proximity to S6 in the I(Ks) channel complex. On the basis of homology modeling that compares the KvLQT1 S6 segment with the structure of the bacterial potassium channel KcsA, we predict that the sulfhydryl side chain of Cys-331 projects away from the central axis of the KvLQT1 pore and suggest that minK resides outside of the permeation pathway. A preliminary model illustrating the orientation of minK with S6 was validated by successful prediction of a novel Cd2+ binding site created within the I(Ks) channel complex by engineering additional cysteine residues into both subunits. Our results indicate the location and orientation of minK within the I(Ks) channel complex and further suggest that Cd2+ exerts its effect on I(Ks) through an allosteric mechanism rather than direct pore blockade.

Animals↗
PubMed1999

Developmental expression of voltage-gated potassium channel beta subunits.

Expression of potassium channel beta subunits (Kvbeta) was determined in the developing mouse CNS using an antiserum against an amino acid sequence present in the C-terminus of Kvbeta1, Kvbeta2, and Kvbeta3. Using the anti-Kvbeta antiserum, we determined that Kvbeta expression is restricted to the spinal cord and dorsal root ganglia in the embryonic CNS. At birth, Kvbeta expression is detected in brainstem and midbrain nuclei, but was not detected in the hippocampus, cerebellum or cerebral cortex. During the first postnatal week, Kvbeta expression is present in hippocampal and cortical pyramidal cells and in cerebellar Purkinje cells. Expression of Kvbeta subunits reaches adult levels by the third postnatal week in all of the brain regions examined. A rabbit antiserum directed against a unique peptide sequence in the N-terminus of the Kvbeta1 protein demonstrates that this subunit displays a novel expression pattern in the developing mouse brain. Kvbeta1 expression is high at birth in all brain regions examined and decreases with age. In contrast, Kvbeta2 expression is low at birth and increases with age to reach adult levels by the third postnatal week. These findings support the notion that the differential regulation of distinct potassium channel beta subunits, in the developing mouse nervous system, may confer the functional diversity required to mediate both neuronal survival and maturation.

Aging↗
PubMed1999

Structural and functional modularity of voltage-gated potassium channels.

Sequence similarity among known potassium channels indicates the voltage-gated potassium channels consist of two modules: the N-terminal portion of the channel up to and including transmembrane segment S4, called in this paper the 'sensor' module, and the C-terminal portion from transmembrane segment S5 onwards, called the 'pore' module. We investigated the functional role of these modules by constructing chimeric channels which combine the 'sensor' from one native voltage-gated channel, mKv1.1, with the 'pore' from another, Shaker H4, and vice versa. Functional studies of the wild type and chimeric channels show that these modules can operate outside their native context. Each channel has a unique conductance-voltage relation. Channels incorporating the mKv1.1 sensor module have similar rates of activation while channels having the Shaker pore module show similar rates of deactivation. This observation suggests the mKv1.1 sensor module limits activation and the Shaker pore module determines deactivation. We propose a model that explains the observed equilibrium and kinetic properties of the chimeric constructs in terms of the characteristics of the native modules and a novel type of intrasubunit cooperativity. The properties ascribed to the modules are the same whether the modules function in their native context or have been assembled into a chimera.

Animals↗
PubMed1985

N-bromoacetamide removes a calcium-dependent component of channel opening from calcium-activated potassium channels in rat skeletal muscle.

Calcium-activated potassium channels from cultured rat skeletal muscle were treated with the protein-modifying reagent N-bromoacetamide (NBA) (0.3-1 mM) and studied in excised patches using patch-clamp techniques. After NBA treatment, channels opened only occasionally, and, in contrast to untreated channels, the open probability was no longer sensitive to intracellular surface calcium ions (1 nM to 100 microM). Channel activity did, however, exhibit a voltage dependence similar in direction and magnitude to that shown before NBA treatment (increasing e-fold with 19 mV depolarization). Distributions of open channel lifetimes revealed that NBA treatment virtually abolished openings of long duration, which suggests that this class of openings requires calcium sensitivity. These effects were not reversed by subsequent washing. Quantitatively similar open probability, voltage dependence, and open-interval distributions were observed in untreated channels in calcium-free medium. These results suggest that NBA removed a calcium-dependent component of channel opening, and that normal channels are able to open in the absence of significant intracellular calcium concentrations.

Acetamides↗
PubMed1998

Characterization of an eag-like potassium channel in human neuroblastoma cells.

1. SH-SY5Y human neuroblastoma cells were investigated with whole-cell and perforated patch recording methods. 2. Besides a quickly activating delayed rectifier channel and a HERG-like channel, a slowly activating potassium channel with biophysical properties identical to those of rat eag (r-eag) channels was detected, here referred to as h-eag. 3. h-eag shows a marked Cole-Moore shift, i.e. the activation kinetics become very slow when the depolarization starts from a very negative holding potential. In addition, extracellular Mg2+ and Ni2+ strongly slow down activation. 4. Application of acetylcholine induces a fast block of the current when recorded in the perforated patch mode. This block is presumably mediated by Ca2+, as about 1 microM intracellular Ca2+ completely abolished h-eag outward current. 5. When cells were grown in the presence of 10 microM retinoic acid in order to synchronize the cell line in the G1 phase of the cell cycle, h-eag current was reduced to less than 5 % of the control value, while the delayed rectifier channel was expressed more abundantly. Down-regulation of h-eag by long-term exposure to retinoic acid was paralleled by a right shift in the activation potential of HERG-like channels. 6. Acute application of 10 microM retinoic acid blocked the delayed rectifier channel but enhanced the h-eag current. 7. Thus, our results show that human neuroblastoma cells express in a cell cycle-dependent manner an [Mg2+]o-dependent potassium channel (h-eag) which is blocked by submicromolar concentrations of intracellular Ca2+.

Acetylcholine↗
PubMed1990

Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias.

Although work on class III antiarrhythmics remains at an early stage, these agents still appear to possess greater efficacy and less proarrhythmia than conventional class I agents in those experimental arrhythmia models considered to be most representative of the clinical situation. Although prolongation of repolarization carries with its own tendency for pause-dependent arrhythmogenesis (i.e., torsade de pointes), available data suggest that this may be a function of nonspecificity in potassium channel block rather than a general characteristic of class III activity. The availability of new and more selective blockers of specific cardiac potassium channels under development as class III agents have already helped to clarify basic questions about the ionic mechanism of repolarization in the heart, and one hopes that a growing clinical data base will eventually determine the relative safety and efficacy of these agents in preventing symptomatic and life-threatening arrhythmias.

Animals↗
PubMed1995

Block of cloned voltage-gated potassium channels by the second messenger diacylglycerol independent of protein kinase C.

1. Diacylglycerols (DAGs) are common intracellular second messengers produced as a result of activation of phospholipase C. We have examined the direct effects of DAG on currents from cloned voltage-dependent potassium channels. Potassium channels were studied by overexpression of their cRNAs in Xenopus oocytes or of their cDNAs in HEK 293 cells, and macroscopic currents were recorded from inside-out membrane patches. 2. When applied to the intracellular side of the patch, 1,2-dioctanoyl-sn-glycerol (C8:0) (DOG) blocks Shaker IR, Kv1.3, and Kv1.6 channels. This block appears macroscopically as a large speeding of the inactivation rate. Longer carbon chain length DAGs (10 and 12 carbons) are less effective in producing this response. 3. DOG is effective at low concentrations, doubling the apparent inactivation rate at 162 nM, and has a fast time course, with a wash-in and reversal to control each within approximately 30 s. 4. Voltage steps delivered with a two pulse protocol in the presence of DOG indicate that recovery from DOG block is voltage dependent. Recovery occurs quickly (tau = 507 ms) when channels are closed quickly by hyperpolarized (-90 mV) potentials, and occurs slowly (tau = 1.3 s) when channels are closed incompletely by depolarized (-60 mV) potentials. 5. The action of DOG is independent of protein kinase C (PKC) activation, because it does not require ATP, nor is it blocked by staurosporin or by the PKC inhibitor peptide 19-36.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Pretreatment with the adenosine triphosphate-sensitive potassium channel opener nicorandil and improved myocardial protection during high-potassium cardioplegic hypoxia.

We hypothesized that pretreatment with the potassium channel opener nicorandil might enhance myocardial protection achieved by cold (20 degrees C) high-potassium (16 mmol/L) cardioplegia (5 ml/min) during long-duration (120 minutes) myocardial hypoxia (average oxygen content 5.4 ml/dl). We tested a 15-minute infusion of nicorandil (1 mmol/L) given only before (group A, n = 8) or before and during cardioplegia (group B, n = 8) in guinea pig papillary muscle preparations contracting isometrically while stimulated (4 mA, 2 msec) at 1600 msec cycle length. Nicorandil was significantly negative inotropic before cardioplegia and shortened significantly action potential duration. During cardioplegia, time to arrest of contraction was shortened from 145 +/- 28 seconds (mean +/- standard error) in the vehicle group (dimethyl sulfoxide 1:100; n = 8) to 56 +/- 10 seconds (p < 0.02) and 68 +/- 5 seconds (p < 0.05) in groups A and B, respectively. Recovery of developed tension at 60 minutes of normothermic reoxygenation (expressed as percent of prehypoxia basal value) was ameliorated from 54% +/- 6% (vehicle group) to 92% +/- 4% (group A, p < 0.01) and to 119% +/- 19% (group B, p < 0.01). The specific potassium channel blocker glibenclamide (glib: 1 mumol/L, n = 8) prolonged action potential duration and was without effect on time to arrest. On reoxygenation, the glib group had prolonged time to half relaxation (versus group A, p < 0.02) and the worst percent developed tension at 60 minutes (40% +/- 4%). In the overall study, time to arrest and percent developed tension at 60 minutes were inversely correlated (r = -0.45, p < 0.01). Arrhythmias were never observed. Multivariate analysis showed that pretreatment with nicorandil (with or without drug adjunct to cardioplegic solution) was a significant factor (r2 = 0.65, p = 0.0001) to influence reoxygenation-mediated recovery of mechanical function. Neither the negative inotropic effect of nicorandil before cardioplegia nor its abbreviating action on time to arrest during cardioplegia was contributory to explain recovery of function on reoxygenation. In subgroup analysis, negative inotropism and the shortening of action potential duration were contributory factors. These data suggest that nicorandil pretreatment activates potassium channels and enhances the myocardial protection provided by cold cardioplegia an effect, which is evident after a long hypoxic period, late on reoxygenation.

Action Potentials↗
PubMed2003

Effect of the KCNQ potassium channel opener retigabine on single KCNQ2/3 channels expressed in CHO cells.

KCNQ2/3 potassium channel subunits were co-expressed in Chinese hamster ovary (CHO) cells and currents through single channels recorded using cell-attached patches. Channels had a similar slope conductance in the presence (8.04 +/- 0.02 pS) and absence (7.6 +/- 0.01 pS) of 10 microM retigabine. The mean maximal open probability (Po) for single KCNQ2/3 channels was 0.13 +/- 0.02, with a half-maximal Po potential (Vo) of -28.7 +/- 1.4 mV for control recordings. Retigabine increased mean maximal Po to 0.38 +/- 0.04 and produced a hyperpolarising shift of Vo to -40.1 +/- 3.4 mV. Single KCNQ2/3 channels have multiple voltage-dependent kinetic components in their activity (CL-OS-CM-OL-CS; C = closed, O = open, L = long, S = short, M = medium), giving short, medium and long closed times (tauCS, tauCM, tauCL) and short and long open times (tauOS and tauOL). In the presence of retigabine at 0 mV the combined duration and contributions of the longest closed time tauCL decreased tenfold, while the short and long open times increased fourfold and twofold, respectively. Thus, steady-state kinetics were modified to favour the open channel configuration.

Animals↗
PubMed2006

[Novel mutations of potassium channel KCNQ1 S145L and KCNH2 Y475C genes in Chinese pedigrees of long QT syndrome].

OBJECTIVE: Hereditary long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of QT interval on electrocardiograms (ECGs) and syncope and sudden death caused by a specific multi-polymorphic ventricular tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in cardiac sodium channel gene SCN5A; potassium channel subunit genes KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2; calcium channel gene Cav2.1. and ankyrin-B gene ANK2. METHODS: We characterized 77 Chinese LQTS patients with clinical manifestations and mutations in the main LQTS genes, KCNQ1 and KCNH2 using PCR and sequence analysis. RESULTS: The spectrum of ST-T-wave patterns of 24 (31.2%) probands were considered as LQT1, 42 (54.5%) as LQT2 and 3 (3.9%) as LQT3. The remaining 8 (10.3%) could not be characterized. The average age for this population of LQTS patients was (27.6 +/- 16.4) years and the average QTc (561 +/- 70) ms, and the age of the first syncopal attack was (17.6 +/- 14.7) years. The triggering factors for cardiac events happening in these mutation carriers included physical exercise, emotional excitement and auditory irritation. We identified 4 KCNQ1 mutations and 7 KCNH2 mutations. Six of them were first identified with some data already shown. In this paper we showed the data of 6 other mutations. CONCLUSIONS: LQT2 is the most common type of LQTS in Chinese; 2 mutations of KCNQ1 and KCNH2 were first identified in this report; there are some differences between Chinese and North American or European LQTS patients in clinical characters and ECG.

Adolescent↗
PubMed1998

[ATP-sensitive potassium channels and substances affecting them].

ATP-sensitive potassium channels are the site of action of the sulphonylurea derivatives that are used to treat non-insulin-dependent diabetes mellitus. These ATP-sensitive potassium channels are also found in myocardial cells and in vascular smooth muscle cells. The sulphonylurea derivatives have been reported to cancel the cardioprotective effects by blocking the opening of these channels in myocardium and vascular smooth muscles. A new sulphonylurea derivative, glimepiride, has been shown to be devoid of vascular ATP-sensitive potassium channel binding properties. The so called potassium-channel-openers, on the other hand, are expected to be used in the treatment of hypertension, ischemic heart disease and asthma bronchiale.

Adenosine Triphosphate↗
PubMed1993

Calcium channels and calcium-gated potassium channels at the frog neuromuscular junction.

Two mechanisms which regulate transmitter release by regulating Ca2+ entry in the presynaptic nerve terminal were studied at the frog neuromuscular junction (nmj). First, the location of Ca2+ channels in relation to transmitter release sites and, second, the regulation of Ca2+ entry by Ca(2+)-gated potassium (gKca) channels. Ca2+ channels were disclosed using fluorescent omega-conotoxin GVIA (omega-CgTX) which blocks transmitter release and Ca2+ entry at the frog nmj. Ca2+ channels were located in bands spaced at regular intervals of 1 micron. The omega-CgTX labeling was removed following mechanical displacement of the presynaptic terminal after collagenase digestion. The bands of omega-CgTX staining matched almost perfectly the staining of cholinergic receptors with fluorescent alpha-bungarotoxin (alpha-BuTX) and therefore must be located at the active zone. The role of gKca channels in the regulation of transmitter release was assessed using charybdotoxin (ChTX) which blocks gKca channels of large and intermediate conductances. Application of ChTX (2-20 nM) induced a two-fold increase in transmitter release which was prevented when a membrane permeant Ca2+ buffer (DMBAPTA-AM) was introduced prior to the toxin application. The Ca2+ buffer by itself caused a reduction in transmitter release. Nerve-evoked Ca2+ entry in the presynaptic terminal, detected with the fluorescent indicator fluo3, was increased following gKca channel blockade by ChTX. The Ca(2+)-gated K+ channels may function to limit the duration of the presynaptic action potential and thus limit Ca2+ entry.

Animals↗
PubMed1999

Single-channel properties of BK-type calcium-activated potassium channels at a cholinergic presynaptic nerve terminal.

1. A high-conductance calcium-activated potassium channel (BK KCa) was characterized at a cholinergic presynaptic nerve terminal using the calyx synapse isolated from the chick ciliary ganglion. 2. The channel had a conductance of 210 pS in a 150 mM:150 mM K+ gradient, was highly selective for K+ over Na+, and was sensitive to block by external charybdotoxin or tetraethylammonium (TEA) and by internal Ba2+. At +60 mV it was activated by cytoplasmic calcium [Ca2+]i with a Kd of approximately 0.5 microM and a Hill coefficient of approximately 2.0. At 10 microM [Ca2+]i the channel was 50 % activated (V) at -8.0 mV with a voltage dependence (Boltzmann slope-factor) of 32.7 mV. The V values hyperpolarized with an increase in [Ca2+]i while the slope factors decreased. There were no overt differences in conductance or [Ca2+]i sensitivity between BK channels from the transmitter release face and the non-release face. 3. Open and closed times were fitted by two and three exponentials, respectively. The slow time constants were strongly affected by both [Ca2+]i and membrane potential changes. 4. In cell-attached patch recordings BK channel opening was enhanced by a prepulse permissive for calcium influx through the patch, suggesting that the channel can be activated by calcium ion influx through neighbouring calcium channels. 5. The properties of the presynaptic BK channel are well suited for rapid activation during the presynaptic depolarization and Ca2+ influx that are associated with transmitter release. This channel may play an important role in terminating release by rapid repolarization of the action potential.

Algorithms↗
PubMed2003

Evidence for intersubunit interactions between S4 and S5 transmembrane segments of the Shaker potassium channel.

Voltage-gated potassium channels are transmembrane proteins made up of four subunits, each comprising six transmembrane (S1-S6) segments. S1-S4 form the voltage-sensing domain and S5-S6 the pore domain with its central pore. The sensor domain detects membrane depolarization and transmits the signal to the activation gates situated in the pore domain, thereby leading to channel opening. An understanding of the mechanism by which the sensor communicates the signal to the pore requires knowledge of the structure of the interface between the voltage-sensing and pore domains. Toward this end, we have introduced single cysteine mutations into the extracellular end of S4 (positions 356 and 357) in conjunction with a cysteine in S5 (position 418) of the Shaker channel and expressed the mutants in Xenopus oocytes. We then examined the propensity of each pair of engineered cysteines to form a metal bridge or a disulfide bridge, respectively, by examining the effect of Cd2+ ions and copper phenanthroline on the K+ conductance of a whole oocyte. Both reagents reduced currents through the S357C,E418C double mutant channel, presumably by restricting the movements necessary for coupling the voltage-sensing function to pore opening. This inhibitory effect was seen in the closed state of the channel and with heteromers composed of S357C and E418C single mutant subunits; no effect was seen with homomers of any of the single mutant channels. These data indicate that the extracellular end of S4 lies in close proximity to the extracellular end of the S5 of the neighboring subunit in closed channels.

Animals↗
PubMed2004

Increased motor drive and sleep loss in mice lacking Kv3-type potassium channels.

The voltage-gated potassium channels Kv3.1 and Kv3.3 are widely expressed in the brain, including areas implicated in the control of motor activity and in areas thought to regulate arousal states. Although Kv3.1 and Kv3.3-single mutants show some physiological changes, previous studies revealed relatively subtle behavioral alterations suggesting that Kv3.1 and Kv3.3 channel subunits may be encoded by a pair of redundant genes. In agreement with this hypothesis, Kv3.1/Kv3.3-deficient mice display a 'strong' mutant phenotype that includes motor dysfunction (ataxia, myoclonus, tremor) and hyperactivity when exposed to a novel environment. In this paper we report that Kv3.1/Kv3.3-deficient mice are also constitutively hyperactive. Compared to wildtype mice, double mutants display 'restlessness' that is particularly prominent during the light period, when mice are normally at rest, characterized by more than a doubling of ambulatory and stereotypic activity, and accompanied by a 40% sleep reduction. When we reinvestigated both single mutants, we observed constitutive increases of ambulatory and stereotypic activity in conjunction with sleep loss in Kv3.1-single mutants but not in Kv3.3-single mutants. These findings indicate that the absence of Kv3.1-channel subunits is primarily responsible for the increased motor drive and the reduction in sleep time.

Animals↗