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PubMed2005

Downregulation of the HERG (KCNH2) K(+) channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation.

The HERG (KCNH2) potassium channel underlies the rapid component of the delayed rectifier current (I(kr)), a current contributing to the repolarisation of the cardiac action potential. Mutations in HERG can cause the hereditary forms of the short-QT and long-QT syndromes, predisposing to ventricular arrhythmias and sudden cardiac death. HERG is expressed mainly in the cell membrane of cardiac myocytes, but has also been identified in cell membranes of a range of other cells, including smooth muscle and neurones. The mechanisms regulating the surface expression have however not yet been elucidated. Here we show, using stable HERG-expressing HEK 293 cells, that ceramide evokes a time-dependent decrease in HERG current which was not attributable to a change in gating properties of the channel. Surface expression of the HERG channel protein was reduced by ceramide as shown by biotinylation of surface proteins, western blotting and immunocytochemistry. The rapid decline in HERG protein after ceramide stimulation was due to protein ubiquitylation and its association with lysosomes. The results demonstrate that the surface expression of HERG is strictly regulated, and that ceramide modifies HERG currents and targets the protein for lysosomal degradation.

Cells, Cultured↗
PubMed2000

Voltage-dependent ion channels in CAD cells: A catecholaminergic neuronal line that exhibits inducible differentiation.

Cell lines derived from tumors engineered in the CNS offer promise as models of specific neuronal cell types. CAD cells are an unusual subclone of a murine cell line derived from tyrosine hydroxylase (TH) driven tumorigenesis, which undergoes reversible morphological differentiation on serum deprivation. Using single-cell electrophysiology we have examined the properties of ion channels expressed in CAD cells. Despite relatively low resting potentials, CAD cells can be induced to fire robust action potentials when mildly artificially hyperpolarized. Correspondingly, voltage-dependent sodium and potassium currents were elicited under voltage clamp. Sodium currents are TTX sensitive and exhibit conventional activation and inactivation properties. The potassium currents reflected two pharmacologically distinguishable populations of delayed rectifier type channels while no transient A-type channels were observed. Using barium as a charge carrier, we observed an inactivating current that was completely blocked by nimodipine and thus associated with L-type calcium channels. On differentiation, three changes in functional channel expression occurred; a 4-fold decrease in sodium current density, a 1.5-fold increase in potassium current density, and the induction of a small noninactivating barium current component. The neuronal morphology, excitability properties, and changes in channel function with differentiation make CAD cells an attractive model for study of catecholaminergic neurons.

Action Potentials↗
PubMed1990

Mechanisms of potassium channel block in rat alveolar epithelial cells.

Block of inactivating delayed rectifier K+ currents was studied in rat alveolar epithelial cells in primary culture using the whole-cell configuration of the gigohm-seal voltage-clamp technique. Charybdotoxin was the only blocker studied which did not alter K+ current kinetics; it produced a simple block (K1 approximately 1 nM) which appeared to be independent of voltage or channel state (open, closed or inactivated). Tetraethylammonium slowed inactivation of K+ currents, consistent with the notion that blocked channels cannot inactivate. Verapamil and methoxyverapamil produced time-, voltage- and concentration-dependent "inactivation" or block of open channels during depolarizing pulses, with negligible block of closed channels at negative holding potentials. Capsaicin, chlorpromazine, phencyclidine, quinidine and tetrahydroaminoacridine both increased the rate of inactivation and decreased the peak K+ current. These characteristics suggest that both open and closed channels can be blocked, but that open channels are blocked preferentially. Nifedipine, like most other blockers, increased the rate of K+ current decay, but, unlike other blockers, resulted in two distinct kinetic components of current decay under some conditions. Because nifedipine is uncharged, the voltage and time-dependence of its block cannot be ascribed to a traditional ionic blockade mechanism. Mechanisms of K+ channel block are compared with block of Ca++ channels by calcium "antagonists" and block of Na+ channels by local anesthetics. Interactions between gating kinetics and K+ channel blockade seem to be the rule rather than the exception.

Animals↗
PubMed2001

Casein kinase 2 determines the voltage dependence of the Kv3.1 channel in auditory neurons and transfected cells.

The Kv3.1 potassium channel can be distinguished from most other delayed rectifier channels by its very high threshold of activation and lack of use-dependent inactivation. This allows neurons that express this channel to fire at very high frequencies. We have now found that this feature of the Kv3.1 channel is strongly influenced by its constitutive phosphorylation by the enzyme casein kinase II. Using stably transfected Chinese hamster ovary cells expressing Kv3.1, we show that Kv3.1 is highly phosphorylated under basal conditions. Whole-cell patch clamp recordings were used to characterize the electrophysiological consequence of dephosphorylation using alkaline phosphatase. This enzyme produced an increase in whole-cell conductance and shifted the voltage dependence of activation to more negative potentials by >20 mV. In addition, a similar shift in the voltage dependence of inactivation was observed. These findings were also confirmed in native Kv3.1 channels expressed in medial nucleus of the trapezoid body (MNTB) neurons. Furthermore, inhibitors of casein kinase 2 mimicked the effect of phosphatase treatment on voltage-dependent activation and inactivation, whereas inhibitors of protein kinase C failed to alter these parameters. The combination of biochemical and electrophysiological evidence suggests that the biophysical characteristics of Kv3.1 that are important to its role in MNTB neurons, allowing them to follow high-frequency stimuli with fidelity, are largely determined by phosphorylation of the channel.

Alkaline Phosphatase↗
PubMed1998

Azimilide dihydrochloride, a novel antiarrhythmic agent.

Azimilide, a novel class III antiarrhythmic agent, blocks both the slowly activating (IKs) and rapidly activating (IKr) components of the delayed rectifier potassium current, which distinguishes it from conventional potassium channel blockers such as sotalol and dofetilide, which block only IKr. Azimilide is being developed to prolong the time to recurrence of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia in patients with and without structural heart disease. Azimilide is also being studied for its role in prevention of sudden cardiac death in high-risk patients after myocardial infarction (MI). Preclinical and clinical studies indicate that azimilide prolongs cardiac refractory period in a dose-dependent manner, as manifested by increases in action potential duration, QTc interval, and effective refractory period. Azimilide does not affect PR or QRS interval and minimally affects hemodynamic properties such as blood pressure and heart rate. Its in vivo effects appear to be rate-independent and are maintained under ischemic or hypoxic conditions, properties of potential clinical significance. Azimilide has shown excellent efficacy (>85%) in suppressing supraventricular arrhythmias in a variety of dog models. It also suppressed complex ventricular arrhythmias in infarcted dogs and, in a sudden death cardiac model, decreased mortality. Azimilide pharmacokinetics are very predictable. The drug is completely absorbed, and the extent of absorption is not affected by food. It can be administered once daily. Clinical data suggest that dose adjustments of azimilide are not required for age, gender, hepatic or renal function, or concomitant use of digoxin or warfarin. Azimilide has a good safety profile in open-label safety studies in >800 supraventricular arrhythmia patients, most with structural heart disease. The incidence of serious adverse events, including torsade de pointes, is low. The rate of patient withdrawal from long-term studies is also encouragingly low. Unlike amiodarone, azimilide has shown no evidence of pulmonary or ocular toxicity. Azimilide is expected to provide a unique new therapy for the prevention of supraventricular arrhythmias and sudden cardiac death when Phase III clinical trials are complete and safety and efficacy are confirmed.

Animals↗
PubMed1998

The effects of barium, dofetilide and 4-aminopyridine (4-AP) on ventricular repolarization in normal and hypertrophied rabbit heart.

The density of potassium channels, including the inward rectifying current (IK1), the delayed rectifying current and the transient outward current have been reported to be decreased in cardiac hypertrophy. However, it is not known whether the effects of specific ionic channel blockers are altered in this setting. The effects of barium chloride, which inhibits IK1, of dofetilide, which inhibits the rapidly activating component of the delayed rectifying current, and 4-aminopyridine, which inhibits the transient outward current, were studied in isolated perfused working rabbit hearts. Cardiac hypertrophy was induced in rabbits by aortic banding. Hearts were removed 43 +/- 8 days after surgery, and electrophysiologic parameters were measured at low (30 cm H2O) and high (100 cm H2O) afterload at base line and during perfusion of barium, dofetilide or 4-aminopyridine. The hearts from banded rabbits weighed more (13.0 +/- 2.3 g) than those from the sham controls (10.0 +/- 1.6 g; P < .001). The action potential duration at 90% repolarization (APD90) was greater in hypertrophied hearts (198 +/- 16 msec) at base line than in control hearts (182 +/- 20 msec; P < .01). Barium (0.025 mM) caused greater prolongation of APD90 in hypertrophied hearts than in control hearts at both low afterload (214 +/- 9 msec vs. 195 +/- 20 msec) and high afterload (200 +/- 10 msec vs. 166 +/- 22 msec, P < .01). This interaction of barium's effects on APD90 and hypertrophy was highly statistically significant (P < .001). In contrast, dofetilide (15 nM) and 4-aminopyridine (1.0 mM) caused similar changes in APD90 in hypertrophied hearts and in control hearts at low afterload and high afterload (P = NS). In isolated ventricular myocytes, IK1 and transient outward densities, but not the rapidly activating component of the delayed rectifying current were decreased in hypertrophied cells compared with control cells (P < .05). Thus the increased effects of barium on prolongation of APD in hypertrophy are probably due to the decreased density of IK1 in hypertrophy and perhaps, in part, to a change in the balance of repolarizing currents that occurs in hypertrophy.

4-Aminopyridine↗
PubMed1993

Exploring parameter space in detailed single neuron models: simulations of the mitral and granule cells of the olfactory bulb.

1. Detailed compartmental computer simulations of single mitral and granule cells of the vertebrate olfactory bulb were constructed using previously published geometric data. Electrophysiological properties were determined by comparing model output to previously published experimental data, mainly current-clamp recordings. 2. The passive electrical properties of each model were explored by comparing model output with intracellular potential data from hyperpolarizing current injection experiments. The results suggest that membrane resistivity in both cells is nonuniform, with somatas having a substantially lower resistivity than the dendrites. 3. The active properties of these cells were explored by incorporating active ion channels into modeled compartments. On the basis of evidence from the literature, the mitral cell model included six channel types: fast sodium, fast delayed rectifier (Kfast), slow delayed rectifier (K), transient outward potassium current (KA), voltage- and calcium-dependent potassium current (KCa), and L-type calcium current. The granule cell model included four channel types: rat brain sodium, K, KA, and the non-inactivating muscarinic potassium current (KM). Modeled channels were based on the Hodgkin-Huxley formalism. 4. Representative kinetics for each of the channel classes above were obtained from the literature. The experimentally unknown spatial distributions of each included channel were obtained by systematic parameter searches. These were conducted in two ways: large-scale simulation series, in which each parameter was varied in turn, and an adaptation of a multidimensional conjugate gradient method. In each case, the simulated results were compared wtih experimental data using a curve-matching function evaluating mean squared differences of several aspects of the simulated and experimental voltage waveforms. 5. Systematic parameter variations revealed a single distinct region of parameter space in which the mitral cell model best fit the data. This region of parameter space was also very robust to parameter variations. Specifically, optimum performance was obtained when calcium and slow K channels were concentrated in the glomeruli, with a lower density in the soma and proximal secondary dendrites. The distribution of sodium and fast potassium channels, on the other hand, was highest at the soma and axon, with a much lighter distribution throughout the secondary dendrites. The KA and KCa channels were also concentrated near the soma. 6. The parameter search of the granule cell model was much less restrained by experimental data. Several parameter regimes were found that gave a good match to the data.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Episodic ataxia results from voltage-dependent potassium channels with altered functions.

Episodic ataxia (EA) is an autosomal dominant human disorder that produces persistent myokymia and attacks of generalized ataxia. Recently, familial EA has been linked to the voltage-dependent delayed rectifier, Kv1.1, on chromosome 12. Six EA families have been identified that carry distinct Kv1.1 missense mutations; all individuals are heterozygous. Expression in Xenopus oocytes demonstrates that two of the EA subunits form homomeric channels with altered gating properties. V408A channels have voltage dependence similar to that of wild-type channels, but with faster kinetics and increased C-type inactivation, while the voltage dependence of F184C channels is shifted 20 mV positive. The other four EA subunits do not produce functional homomeric channels but reduce the potassium current when coassembled with wild-type subunits. The results suggest a cellular mechanism underlying EA in which the affected nerve cells cannot efficiently repolarize following an action potential because of altered delayed rectifier function.

Animals↗
PubMed2002

A modelling study of locomotion-induced hyperpolarization of voltage threshold in cat lumbar motoneurones.

During fictive locomotion the excitability of adult cat lumbar motoneurones is increased by a reduction (a mean hyperpolarization of approximately 6.0 mV) of voltage threshold (Vth) for action potential (AP) initiation that is accompanied by only small changes in AP height and width. Further examination of the experimental data in the present study confirms that Vth lowering is present to a similar degree in both the hyperpolarized and depolarized portions of the locomotor step cycle. This indicates that Vth reduction is a modulation of motoneurone membrane currents throughout the locomotor state rather than being related to the phasic synaptic input within the locomotor cycle. Potential ionic mechanisms of this locomotor-state-dependent increase in excitability were examined using three five-compartment models of the motoneurone innervating slow, fast fatigue resistant and fast fatigable muscle fibres. Passive and active membrane conductances were set to produce input resistance, rheobase, afterhyperpolarization (AHP) and membrane time constant values similar to those measured in adult cat motoneurones in non-locomoting conditions. The parameters of 10 membrane conductances were then individually altered in an attempt to replicate the hyperpolarization of Vth that occurs in decerebrate cats during fictive locomotion. The goal was to find conductance changes that could produce a greater than 3 mV hyperpolarization of Vth with only small changes in AP height (< 3 mV) and width (< 1.2 ms). Vth reduction without large changes in AP shape could be produced either by increasing fast sodium current or by reducing delayed rectifier potassium current. The most effective Vth reductions were achieved by either increasing the conductance of fast sodium channels or by hyperpolarizing the voltage dependency of their activation. These changes were particularly effective when localized to the initial segment. Reducing the conductance of delayed rectifier channels or depolarizing their activation produced similar but smaller changes in Vth. Changes in current underlying the AHP, the persistent Na(+) current, three Ca(2+) currents, the "h" mixed cation current, the "A" potassium current and the leak current were either ineffective in reducing Vth or also produced gross changes in the AP. It is suggested that the increased excitability of motoneurones during locomotion could be readily accomplished by hyperpolarizing the voltage dependency of fast sodium channels in the axon hillock by a hitherto unknown neuromodulatory action.

Animals↗
PubMed2005

Protein trafficking abnormalities: a new mechanism in drug-induced long QT syndrome.

Drug induced long QT syndrome (LQTS) can lead to cardiac arrhythmias and sudden death, and has emerged as a worldwide problem. Most drugs that cause this are thought to directly block a specific cardiac ion channel (KCNH2 or hERG) that carries the rapidly activating delayed rectifier potassium current, I(Kr). In this issue of the British Journal of Pharmacology, evidence is presented to support a new mechanism for causing drug induced LQTS. The drug pentamidine, at near therapeutic concentrations that do not cause direct KCNH2 channel block, disrupts normal KCNH2 channel protein processing and maturation to reduce its surface membrane expression. This indirect mechanism for reducing I(Kr) is novel, and whether other drugs may cause similar protein trafficking abnormalities is largely unknown.

Antiprotozoal Agents↗
PubMed2000

The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization.

1. The relative contributions of the rapid and slow components of the delayed rectifier potassium current (IKr and IKs, respectively) to dog cardiac action potential configuration were compared in ventricular myocytes and in multicellular right ventricular papillary muscle and Purkinje fibre preparations. Whole-cell patch-clamp techniques, conventional microelectrode and in vivo ECG measurements were made at 37C. 2. Action potential duration (APD) was minimally increased (less than 7%) by chromanol 293B (10 microM) and L-735,821 (100 nM), selective blockers of IKs, over a range of pacing cycle lengths (300-5000 ms) in both dog right ventricular papillary muscles and Purkinje fibre strands. D-Sotalol (30 microM) and E-4031 (1 microM), selective blockers of IKr, in the same preparations markedly (20-80%) lengthened APD in a reverse frequency-dependent manner. 3. In vivo ECG recordings in intact anaesthetized dogs indicated no significant chromanol 293B (1 mg kg-1 i.v.) effect on the QTc interval (332.9 +/- 16.1 ms before versus 330.5 +/- 11.2 ms, n = 6, after chromanol 293B), while D-sotalol (1 mg kg-1 i.v.) significantly increased the QTc interval (323.9 +/- 7.3 ms before versus 346.5 +/- 6.4 ms, n = 5, after D-sotalol, P < 0.05). 4. The current density estimated during the normal ventricular muscle action potential (i.e. after a 200 ms square pulse to +30 mV or during a 250 ms long 'action potential-like' test pulse) indicates that substantially more current is conducted through IKr channels than through IKs channels. However, if the duration of the square test pulse or the 'action potential-like' test pulse was lengthened to 500 ms the relative contribution of IKs significantly increased. 5. When APD was pharmacologically prolonged in papillary muscle (1 microM E-4031 and 1 microg ml-1 veratrine), 100 nM L-735,821 and 10 microM chromanol 293B lengthened repolarization substantially by 14.4 +/- 3.4 and 18. 0 +/- 3.4% (n = 8), respectively. 6. We conclude that in this study IKs plays little role in normal dog ventricular muscle and Purkinje fibre action potential repolarization and that IKr is the major source of outward current responsible for initiation of final action potential repolarization. Thus, when APD is abnormally increased, the role of IKs in final repolarization increases to provide an important safety mechanism that reduces arrhythmia risk.

Action Potentials↗
PubMed1996

Functional characterization of Kv channel beta-subunits from rat brain.

1. The potassium channel beta-subunit from rat brain, Kv beta 1.1, is known to induce inactivation of the delayed rectifier channel Kv1.1 and Kv1.4 delta 1-110. 2. Kv beta 1.1 was co-expressed in Xenopus oocytes with various other potassium channel alpha-subunits. Kv beta 1.1 induced inactivation in members of the Kv1 subfamily with the exception of Kv 1.6; no inactivation of Kv 2.1, Kv 3.4 delta 2-28 and Kv4.1 channels could be observed. 3. The second member of the beta-subunit subfamily, Kv beta 2, had a shorter N-terminal end, accelerated inactivation of the A-type channel Kv 1.4, but did not induce inactivation when co-expressed with delayed rectifiers of the Kv1 channel family. 4. To test whether this subunit co-assembles with Kv alpha-subunits, the N-terminal inactivating domains of Kv beta 1.1 and Kv beta 3 were spliced to the N-terminus of Kv beta 2. The chimaeric beta-subunits (beta 1/ beta 2 and beta 3/ beta 2) induced fast inactivation of several Kv1 channels, indicating that Kv beta 2 associates with these alpha-subunits. No inactivation was induced in Kv 1.3, Kv 1.6, Kv2.1 and Kv3.4 delta 2-28 channels. 5. Kv beta 2 caused a voltage shift in the activation threshold of Kv1.5 of about -10 mV, indicating a putative physiological role. Kv beta 2 had a smaller effect on Kv 1.1 channels. 6. Kv beta 2 accelerated the activation time course of Kv1.5 but had no marked effect on channel deactivation.

Animals↗
PubMedDate not supplied

Lead (Pb2+) modulation of potassium currents of guinea pig outer hair cells.

Outer hair cells (OHC) are mechanosensitive sensory cells of the inner ear cochlea and are involved in modulating the activity of inner hair cells in the transduction of an acoustic stimulus. Potassium (K(+)) currents play an important role in the sensory transduction process. K(+) currents were recorded from acutely dissociated OHC obtained from the guinea pig organ of Corti. The whole-cell patch clamp technique was employed. We identified a channel that exhibited outward current of the delayed rectifier type (Kv). Kv channels mediating inward currents carried by potassium ions were also identified and took on the appearance of a previously described inwardly rectifying current. Lead (Pb(2+)) acetate at concentrations of 0.1, 1.0, 10, and 100 microM was bath applied. Time to activation for outward-going current was not affected by Pb(2+). The time course of Pb(2+) effects was seen as a dose-dependent reduction of K(+) current over time, with very little or no recovery after washout. Pb(2+) inhibited the outward Kv relative current with values of 0.10, 0.14, 0.18, and 0.30 at 0.1, 1.0, 10, and 100 microM, respectively. Pb(2+) did not modulate time to activation, peak current, or inactivation of inward I(K). The effects of Pb(2+) on the potassium currents of OHC are not remarkable and therefore OHC are probably not a major cause of purported peripheral hearing loss observed in Pb(2+)-exposed animals and humans.

Animals↗
PubMed1987

Cyclic AMP-modulated potassium channels in murine B cells and their precursors.

A voltage-dependent potassium current (the delayed rectifier) has been found in murine B cells and their precursors with the whole-cell patch-clamp technique. The type of channel involved in the generation of this current appears to be present throughout all stages of pre-B-cell differentiation, since it is detected in pre-B cell lines infected with Abelson murine leukemia virus; these cell lines represent various phases of B-cell development. Thus, the presence of this channel is not obviously correlated with B-cell differentiation. Although blocked by Co2+, the channel, or channels, does not appear to be activated by Ca2+ entry. It is, however, inactivated by high intracellular Ca2+ concentrations. In addition, elevation of intracellular adenosine 3', 5'-monophosphate induces at all potentials a rapid decrease in the peak potassium conductance and increased rates of activation and inactivation. Therefore, potassium channels can be physiologically modulated by second messengers in lymphocytes.

Animals↗
PubMed1996

The long QT syndrome: new diagnostic and therapeutic approach in the era of molecular biology.

The idiopathic long QT syndrome is a congenital disease characterized by prolongation of the QT interval and by stress-induced syncopal episodes caused by the development of "torsades de pointes". Over the last decade, the great advances in the field of molecular biology have made it possible to elucidate the genetic causes of the disease. In particular, three genes have been implicated in the pathogenesis of the disease: SCN5A (LQT3), encoding for the cardiac sodium channel and located on chromosome 3, HERG (LQT2), encoding for a cardiac potassium channel (Ikr) and located on chromosome 7 and KVLQT1 (LQT1), located on chromosome 11 and encoding for a cardiac potassium channel whose electrophysiologic profile is still undefined. Within each of these genes several different mutations have been identified and subsequently expressed to determine the electrophysiological changes induced by the mutation in the normal function of the channels. These studies have suggested that LQT3 is caused by alterations in the inactivation of cardiac sodium channels while LQT2 is caused by a reduction in the delayed rectifier potassium current. Based on this evidence, we developed the first cellular model for LQTS in order to provide a mean of assessing the effect of different interventions in two different forms of disease, LQT2 and LQT3. We exposed guinea pig ventricular myocytes to anthopleurin, a toxin that interferes with the inactivation of INa, and to dofetilide, a selective blocker of Ikr, obtaining a prolongation of cellular repolarization with both drugs. We then exposed cells to a Na+ channel blocker, mexiletine, which significantly reduced APD in cells treated with anthopleurin while it did not modify the prolongation induced by dofetilide. In addition, anthopleurin-treated cells demonstrated a greater shortening of APD to rapid pacing than both control and dofetilide-treated cells. Based on this experimental evidence, we tested the same therapeutic interventions, mexiletine and pacing, in fifteen genetically characterized LQTS patients. Mexiletine significantly shortened the QT interval in LQT3 patients but not in LQT2 patients. When we examined the response to an increase in heart rate, we found that LQT3 patients had a more shortened QT interval in response to heart rate changes than LQT2 patients and than healthy controls.

Animals↗
PubMed2001

Synthesis and activity of novel and selective I(Ks)-channel blockers.

Since the discovery of the I(Ks)-potassium channel as the slowly activating component of the delayed rectifier current (I(k)) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K(ATP)-channel openers of the chromanol type we found that chromanol 293B was able to block I(Ks). Chromanol 293B is a sulfonamide analogue of the K(ATP)-channel openers but had no activity on this target. Experiments were initiated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the sulfonamide group were prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.

Animals↗
PubMed2006

Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2.

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by constant muscle rippling movements (myokymia) and episodic attacks of ataxia. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene KCNA1 (hKv1.1), which alter the delayed-rectifier function of the channel. Shaker-like channels of different cell types may be formed by unique hetero-oligomeric complexes comprising Kv1.1, Kv1.4 and Kvbeta1.x subunits. Here we show that the human Kvbeta1.1 and Kvbeta1.2 subunits modulated the functional properties of tandemly linked Kv1.4-1.1 wild-type channels expressed in Xenopus laevis oocytes by (i) increasing the rate and amount of N-type inactivation, (ii) slowing the recovery rate from inactivation, (iii) accelerating the cumulative inactivation of the channel and (iv) negatively shifting the voltage dependence of inactivation. To date, the role of the human Kv1.4-1.1, Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2 channels in the aetiopathogenesis of EA1 has not been investigated. Here we also show that the EA1 mutations E325D, V404I and V408A, which line the ion-conducting pore, and I177N, which resides within the S1 segment, alter the fast inactivation and repriming properties of the channels by decreasing both the rate and degree of N-type inactivation and by accelerating the recovery from fast inactivation. Furthermore, the E325D, V404I and I177N mutations shifted the voltage dependence of the steady-state inactivation to more positive potentials. The results demonstrate that the human Kvbeta1.1 and Kvbeta1.2 subunits regulate the proportion of wild-type Kv1.4-1.1 channels that are available to open. Furthermore, EA1 mutations alter heteromeric channel availability which probably modifies the integration properties and firing patterns of neurones controlling cognitive processes and body movements.

Action Potentials↗
PubMed2004

Andersen syndrome: the newest variant of the hereditary-familial long QT syndrome.

Andersen's Syndrome is a rare disease, hereditary with autosomal dominant transmission, of the ion channels of the sarcolemmal membranes of the cardiac and skeletal muscles (channelopathy), which affects chromosome 17 of the KCNJ2 gene, responsible for encoding the outward potassium delayed rectifier current KIR2.1, resulting in a loss or suppression of the function of this channel.

Action Potentials↗