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PubMed2000

Molecular evidence for a role of Shaw (Kv3) potassium channel subunits in potassium currents of dog atrium.

We previously described an ultrarapid delayed rectifier current in dog atrial myocytes (IKur,d) with properties resembling currents reported for Kv3.1 channels in neural tissue; however, there was no direct molecular evidence for Shaw subfamily (Kv3) subunit expression in the heart. To identify the molecular basis of IKur,d, we cloned a full-length cDNA (dKv3.1) from canine atrium with homology-based reverse transcription (RT)- polymerase chain reaction (PCR) cloning techniques. A 1755 bp full-length cDNA (dKv3.1) was obtained, with 94.2 % homology to rat brain Kv3.1 (rbKv3.1). The deduced amino acid sequence had 99.3 % homology with rbKv3.1. Heterologous expression of dKv3.1 in Xenopus oocytes produced currents with activation voltage dependence, rectification, and activation and deactivation kinetics that strongly resemble native IKur,d. Like IKur,d, dKv3.1 was found to be highly sensitive to extracellular 4-aminopyridine (4-AP) and tetraethylammonium (TEA). RNase protection assays, Western blots and immunohistochemical studies demonstrated the presence of dKv3.1 transcripts and proteins in dog atrial preparations and isolated canine atrial myocytes. Protein corresponding to the Kv1.5 subunit, which can also carry ultrarapid delayed rectifier current, was absent. Unlike neural tissues, which express two splice variants (Kv3.1a and Kv3.1b), canine atrium showed only Kv3.1b transcripts. Whole-cell patch-clamp studies showed that IKur,d is absent in canine ventricular myocytes, and immunohistochemical and Western blot analysis demonstrated the absence of dKv3.1 protein in canine ventricle. We conclude that the Shaw-type channel dKv3.1 is present in dog atrium, but not ventricle, and is the likely molecular basis of canine atrial IKur,d.

4-Aminopyridine↗
PubMed1995

Beta-adrenergic modulation of glial inwardly rectifying potassium channels.

Cultured spinal cord astrocytes (2-13 days in vitro) express several different potassium current types, including delayed rectifier, transient A-type, and inward rectifier (Kir) K+ currents. Of these, Kir is believed to be of critical importance in the modulation of extracellular [K+] in the CNS. Using the whole-cell patch-clamp technique, we analyzed modulation of Kir currents by beta-adrenergic receptor activation. The selective beta-adrenergic agonist isoproterenol (1-100 microM) and epinephrine (1-100 microM) each reduced peak Kir current amplitudes to 52.7 +/- 12.5 and 63.6 +/- 7.0%, respectively, at 100 microM. Forskolin (KD of approximately 25 microM), an activator of adenylate cyclase (AC), and dibutyryl-cyclic AMP (1 mM), a membrane-permeable analogue of cyclic AMP (cAMP), were each used to increase [cAMP]i, the product of AC, and resulted in similar reductions of Kir currents. By contrast, 1,9-dideoxyforskolin (1-50 microM), a forskolin analogue that does not activate AC, did not affect Kir currents, indicating that AC activity is a required element for Kir modulation. Three inhibitors of PKA--Rp-adenosine 3',5'-cyclic monophosphothioate, H-7, and adenosine 3',5'-cyclic monophosphate-dependent protein kinase inhibitor--failed to inhibit Kir current reduction by beta-adrenergic agonists. These results indicate that beta-adrenergic receptor ligands can modulate Kir currents and suggest that this modulation involves activation of AC but not protein kinase A. Such modulation may provide a mechanism by which neurons can modulate glial Kir currents and thereby may affect glial K+ "spatial buffering" in the CNS.

Adenylyl Cyclases↗
PubMedDate not supplied

Unique interaction of scorpion toxins with the hERG channel.

ERG potassium channels specify one component of the delayed rectifier in the heart and are likely to play an important functional role in other excitable cells. Compared to other K+ channels, the human ERG (hERG) channel possesses an unusually long S5-P linker that presumably forms an alpha-helix important for channel function. hERG-specific toxins bind to the outer mouth of the hERG channel. Channel residues in the middle of the S5-P linker and at the pore entrance are critical for toxin binding. One of these scorpion toxins is BeKm-1. Residues critical for BeKm-1 binding to the hERG channel are located in the alpha-helix and the following loop, whereas the "traditional" interaction surface of other short scorpion toxins is formed by residues on the beta-sheet. This unique localization of BeKm-1's interaction surface and its specific action on the hERG channel suggest a unique outer mouth structure of the hERG channel. We used the mutant cycle analysis approach to define contacts in the toxin-channel complex. This information provides critical constraints and is important for molecular modeling of the hERG pore structure.

Animals↗
PubMed2005

In vivo cardiac electrophysiologic effects of a novel diphenylphosphine oxide IKur blocker, (2-Isopropyl-5-methylcyclohexyl) diphenylphosphine oxide, in rat and nonhuman primate.

The voltage-gated potassium channel, Kv1.5, which underlies the ultrarapid delayed rectifier current, I(Kur), is reported to be enriched in human atrium versus ventricle, and has been proposed as a target for novel atrial antiarrhythmic therapy. The administration of the novel I(Kur) blocker (2-isopropyl-5-methyl-cyclohexyl) diphenylphosphine oxide (DPO-1) (0.06, 0.2, and 0.6 mg/kg/min i.v. x 20 min; total doses 1.2, 4.0, and 12.0 mg/kg, respectively) to rat, which exhibits I(Kur) in both atria and ventricle, elicited significant, dose-dependent increases in atrial and ventricular refractory period (9-42%) at all doses tested, with no changes in cardiac rate or indices of cardiac conduction. Plasma levels achieved in rat at the end of the three infusions were 1.1, 4.1, and 7.7 microM. Reverse transcription-polymerase chain reaction analysis of African green monkey atria and ventricle demonstrated an atrial preferential distribution of Kv1.5 transcript. The administration of DPO-1 (1.0, 3.0, and 10.0 mg/kg i.v.; 5-min infusions) to African green monkey elicited significant increases in atrial refractoriness (approximately 15% increase at the 10.0 mg/kg dose), with no change in ventricular refractory period, ECG intervals, heart rate, or blood pressure. Plasma levels of DPO-1 achieved in African green monkey were 0.58, 1.12, and 5.43 microM. The concordance of effect of DPO-1 on myocardial refractoriness with distribution of Kv1.5 in these two species is consistent with the I(Kur) selectivity of DPO-1 in vivo. Moreover, the selective increase in atrial refractoriness in primate supports the concept of I(Kur) blockade as an approach for the development of atrial-specific antiarrhythmic agents.

Animals↗
PubMed1990

K+ current diversity is produced by an extended gene family conserved in Drosophila and mouse.

The Drosophila Shaker gene on the X chromosome has three sister genes, Shal, Shab, and Shaw, which map to the second and third chromosomes. This extended gene family encodes voltage-gated potassium channels with widely varying kinetics (rate of macroscopic current activation and inactivation) and voltage sensitivity of steady-state inactivation. The differences in the currents of the various gene products are greater than the differences produced by alternative splicing of the Shaker gene. In Drosophila, the transient (A current) subtype of the potassium channel (Shaker and Shal) and the delayed-rectifier subtype (Shab and Shaw) are encoded by homologous genes, and there is more than one gene for each subtype of channel. Homologs of Shaker, Shal, Shab, and Shaw are present in mammals; each Drosophila potassium-channel gene may be represented as a multigene subfamily in mammals.

Amino Acid Sequence↗
PubMedDate not supplied

Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis?

Membrane receptors and ion transport mechanisms probably have an important role in lymphocyte activation leading to T-lymphocyte proliferation in the immune response. Here we have applied a gigaohm-seal patch clamp technique to reveal the identity and properties of ion channels in human T lymphocytes. A voltage-dependent potassium channel bearing a resemblance to the delayed rectifier of nerve and muscle cells was found to be the predominant ion channel in these cells. In the whole cell recording conformation, the channels open with sigmoid kinetics during depolarizing voltage steps, reaching a maximum K+ conductance of 3-5 nS. The current subsequently becomes almost completely inactivated during a long-lasting depolarization. Currents through single K+ channels recorded in whole cell and outside-out patch recording conformations reveal a unitary channel conductance of about 16 pS in normal Ringer solution. Thus, the peak current corresponds to approximately 200-300 conducting K+ channels per cell. Phytohaemagglutinin (PHA), at concentrations that produce mitogenesis, alters K+ channel gating within 1 min of addition to the bathing solution, causing channels to open more rapidly and at more negative membrane potentials. 3H-thymidine incorporation by T lymphocytes following PHA stimulation is inhibited by the 'classical' K+ channel blockers tetraethylammonium and 4-aminopyridine, and also by quinine, at doses found to block the K+ channel in voltage-clamped T lymphocytes, suggesting that K+ channels may play a part in mitogenesis.

Calcium↗
PubMed1999

Inhibition of neuronal KV potassium currents by the antidepressant drug, fluoxetine.

1. The effect of the antidepressant drug, fluoxetine on neuronal delayed rectifier (KV) potassium (K) currents was investigated using perforated-patch whole-cell electrophysiological recording methods. 2. Fluoxetine was an effective inhibitor of KV currents in cerebellar granule neurons (CGNs) and also inhibited recombinant KV1.1 channels expressed in Chinese hamster ovary (CHO) cells. 3. Fluoxetine had an IC50 of 11 microM in CGNs but was slightly less potent on KV1.1 channels (IC50=55 microM). Interestingly, fluoxetine was a much more potent inhibitor of KV1.1 expressed in mammalian cells than has been found previously for the same homomeric channel expressed in Xenopus oocytes. 4. At concentrations that produced around 50% block, the shape of the KV currents in the presence of fluoxetine was simply scaled down when compared to control currents. 5. The effect of fluoxetine on KV currents in CGNs was neither voltage-dependent nor dependent on the channels being in their open state. Both of these observations suggest that fluoxetine does not act as a simple open channel blocking agent. 6. It is concluded that block of KV currents in mammalian neurons can occur at therapeutic levels of fluoxetine. This could lead to an increase in neuronal excitability and this effect may contribute to the therapeutic antidepressant action of fluoxetine.

Animals↗
PubMed2004

Prokineticin 2 modulates the excitability of subfornical organ neurons.

The recent discovery of prokineticin 2 (PK2) expression in the suprachiasmatic nucleus and its receptors in critical autonomic control centers of the brain, including the subfornical organ (SFO), suggests the intriguing possibility that PK2 regulates the excitability of SFO neurons and thus influences autonomic function. Using current-clamp techniques to record from dissociated SFO neurons, we examined the effects of PK2 on the excitability of these cells. PK2 (20 nm) induced depolarizations in 40% of SFO neurons (n = 45; mean, 7.5 +/- 1.7 mV), an effect that was reversible, PK2-specific, and concentration dependent. The depolarization was accompanied by an increase in action potential frequency from 0.4 +/- 0.1 to 1.4 +/- 0.5 Hz in responding cells (n = 10). This excitatory effect appears to be, in part, attributable to a PK2-induced decrease in the delayed rectifier potassium current (I(K)). In 10 SFO neurons recorded using perforated patch voltage-clamp techniques, six demonstrated a reversible decrease in I(K) (mean decrease, 26.7 +/- 6.4%) in response to 20 nm PK2, whereas artificial CSF alone was without an effect on these currents. These data are the first to show excitatory effects of PK2 on neurons and, in addition, demonstrate that this peptide modulates voltage-activated K(+) channels. The activation of SFO neurons by PK2 illustrates a mechanism through which this peptide may exert circadian control of autonomic functions.

Action Potentials↗
PubMed2001

The role of endothelium-derived hyperpolarizing factor in the regulation of the uterine circulation in pregnant rats.

OBJECTIVE: The purpose of this study was to determine whether endothelium-derived hyperpolarizing factor regulates rat uterine circulation in pregnant rats. STUDY DESIGN: Intact isolated uterine vascular beds from late pregnant rats were perfused in situ with Krebs buffer that contained dextran, indomethacin, N-nitro-L-arginine methyl ester, and phenylephrine. Endothelium-derived hyperpolarizing factor-induced decreases in perfusion pressure in response to acetylcholine were analyzed. RESULTS: The decrease in perfusion pressure induced by endothelium-derived hyperpolarizing factor was significantly attenuated by 4-aminopyridine and was abolished by a combination of 4-aminopyridine and tetraethylammonium. Endothelium-derived hyperpolarizing factor-induced decrease in perfusion pressure was abolished by potassium chloride and attenuated by miconazole, but not linoleyl hydroxamic acid. Endothelium-derived hyperpolarizing factor-induced decrease in perfusion pressure persisted after perfusion with solutions that contained 2 inhibitors of nitric oxide synthase and a scavenger of nitric oxide. Nitric oxide exerted negative feedback on the endothelium-derived hyperpolarizing factor effects. CONCLUSION: In the pregnant rat uterine vascular beds, endothelium-derived hyperpolarizing factor release is activated by a delayed rectifier type of voltage-sensitive potassium channel. Endothelium-derived hyperpolarizing factor does not seem to be related to nitric oxide or to products of lipoxygenase or cytochrome p450 mono-oxygenase pathways of arachidonic acid metabolism.

Acetylcholine↗
PubMed1999

New advances in class III antiarrhythmic drug therapy.

During the past 10 years there has been a major shift in antiarrhythmic drug development from class I to class III antiarrhythmic agents. The first two class III antiarrhythmic drugs that became available, sotalol and amiodarone, also have potent antiadrenergic actions. Newer antiarrhythmic drugs either block a specific ionic current (e.g., dofetilide-induced blockade of the rapidly activating component of the delayed rectifier potassium current) or block multiple ionic channels (e.g., ibutilide and azimilide) in order to prolong atrial and ventricular action potentials without other specific pharmacologic effects. Recent data suggest that these new class III antiarrhythmic drugs are highly effective for treating patients with rhythm disorders with an acceptable degree of proarrhythmia. This manuscript reviews the newer class III agents' effectiveness in treating atrial and ventricular arrhythmias and the recent studies examining drug-induced prolongation of atrial repolarization to prevent or terminate postoperative atrial fibrillation.

Anti-Arrhythmia Agents↗
PubMed1999

The QT interval and torsade de pointes.

The QT interval on the electrocardiogram is the time from the onset of ventricular depolarisation (the Q wave) to completion of repolarisation (the end of the T wave). It is influenced by heart rate, autonomic factors, electrolyte levels, gender and age. Aprolonged QT interval indicates an increased risk of developing malignant ventricular tachyarrhythmias, particularly torsade de pointes. QT prolongation may be primary (inherited, familial, congenital, idiopathic) or caused by disease, drugs or toxins. Drugs that have been associated with the development of torsade de pointes include antiarrhythmic, antibacterial and psychotropic agents and antihistamines. Several of these drugs depress myocardial ion channels, particularly the rapidly activating delayed rectifier (repolarising) potassium current (I(Kr)). Overdosage of drugs that affect the delayed rectifier (repolarising) potassium currents (I(K)), or coadministration of these drugs with another medication that inhibits their metabolism (e.g. an antihistamine such as terfenadine with an antifungal agent such as ketoconazole, which inhibits the cytochrome P450 3A4 hepatic enzyme), can induce torsade de pointes. Torsade de pointes is a potentially life-threatening ventricular tachyarrhythmia and the risks of administering drugs that can induce this condition must be carefully considered.

Animals↗
PubMed2002

Current and new drugs for the treatment of arrhythmias.

Sudden cardiac death is a leading cause of mortality in industrialized nations, accountingfor 50% of all cardiovascular deaths. Carefully performed randomized trials, technological advances and better understanding of arrhythmia mechanisms have resulted in improved approaches to rhythm disturbances. Risk assessment has to be individualized and can be approached through an analysis based upon all other clinical characteristics of the patient. The need for long-term therapy must be carefully individualized to each patient, since the severity and importance of symptoms are highly variable. This review will summarize the classification of antiarrhythmic drugs and main pharmacokinetic properties. Newer antiarrhythmic drugs either block a specific ionic current (eg, dofetilide-induced blockade of the rapidly activating component of the delayed rectifier potassium current) or block multiple ionic channels (eg, ibutilide and azimilide) in order to prolong atrial and ventricular action potentials without other specific pharmacological effects. Additionally, this manuscript reviews the newer class III agents' effectiveness in treating atrial and ventricular arrhythmias, and the development of novel antiarrhythmic drugs that act specifically to alter cell communication.

Animals↗
PubMed1995

Influence of permeating ions on potassium channel block by external tetraethylammonium.

1. Block by external tetraethylammonium (TEA) was examined on currents carried by potassium (K+) and sodium (Na+) through the cloned delayed rectifier K+ channel Kv2.1. 2. In the presence of high intracellular K+ and high extracellular Na+, currents through the Kv2.1 channel were carried almost exclusively by K+. In the absence of both intracellular and extracellular K+, large currents were carried by Na+ through the Kv2.1 channel. 3. External application of 30 mM TEA blocked K+ currents through Kv2.1 by 87%. The same external concentration of TEA had no effect on Na+ currents through this channel. 4. As the K+ concentration was increased between 0 and 140 mM, the percentage of current blocked by TEA progressively increased from 0 to 87%. 5. These data indicate that block of K+ channels by external TEA depends on the permeating ion. Furthermore, these data indicate that in the presence of Na+ and absence of K+, TEA does not bind to the channel, and that addition of low concentrations of K+ facilitates TEA binding.

Animals↗
PubMed2004

Comparison of modulation of Kv1.3 channel by two receptor tyrosine kinases in olfactory bulb neurons of rodents.

Activation of the receptor tyrosine kinase (RTK), insulin (IRK) or neurotrophin B (TrkB), was characterized and compared in olfactory bulb neuron (OBN) cultures from Sprague Dawley rats and sv129 B6 mice. Current suppression attributed to modulation of the delayed rectifier, Kv1.3, a voltage-gated potassium (Kv) channel of the Shaker family, was observed following acute application of the growth factors, insulin or brain-derived neurotrophic factor (BDNF), to mitral cells of either rodent model. Using site-directed mutagenesis of putative tyrosine phosphorylation recognition motifs in the channel, we find that stimulation of Kv1.3 with these growth factors causes multiple phosphorylation, albeit via different residue combinations that are RTK specific.

Animals↗
PubMed1995

Physical and genetic localization of a Shab subfamily potassium channel (KCNB1) gene to chromosomal region 20q13.2.

A human delayed rectifier K+ channel gene has been localized to the long arm of human chromosome 20q13.2 by fluorescence in situ hybridization of genomic P1 clones from this locus. A polymorphic (GA) microsatellite repeat was identified in one of the P1 clones. The new SSR marker (D20S436) was genotyped in four CEPH pedigrees. Two-point linkage analysis indicated linkage of this marker to a PCR marker, D20S109, with a maximum lod score of 9.32 at theta = 0.001. The assignment of this K+ channel gene to 20q13.2 eliminates it as a candidate for the gene associated with benign familial neonatal convulsions (BFNC), which has been localized to 20q13.3. Genetically, the K+ channel gene maps more than 30 cM proximal to the BFNC locus.

Base Sequence↗
PubMed1999

Effect of verapamil enantiomers and metabolites on cardiac K+ channels expressed in Xenopus oocytes.

The effect of verapamil and its enantiomers and metabolites on cardiac action potential repolarizing potassium channels was tested. For this purpose, the potassium channels Kv1.1, Kv1.5, Kir2.1, and HERG, and the IsK subunit of the IKs-channel complex were expressed in Xenopus oocytes and two-electrode voltage-clamp experiments were performed. Verapamil induced a concentration-dependent block of Kv1. 1-, Kv1.5-, IKs-, and HERG-induced currents with IC50 values of 14.0 +/- 2.7 microM (n = 4), 5.1 +/- 0.5 microM (n = 6), 161.0 +/- 26.3 microM (n = 4), and 3.8 +/- 0.2 microM (n = 5), respectively. The same potency of HERG channel inhibition was observed for the optical enantiomers (+)-verapamil (IC50 = 3.5 +/- 0.4 microM, n = 5) and (-)-verapamil (IC50 = 4.0 +/- 0.7 microM, n = 4), as well as the derivatives norverapamil (D591; IC50 = 3.8 +/- 0.3 microM, n = 4) and D703 (IC50 = 2.2 +/- 0.4 microM, n = 4). The verapamil metabolites D620 and D617 did not block HERG-induced currents at concentrations of up to 30 microM (n = 3). These results demonstrate that cardiac delayed rectifier potassium currents are sensitive targets to calcium channel blockers.

Animals↗
PubMed2001

Functional consequences of the arrhythmogenic G306R KvLQT1 K+ channel mutant probed by viral gene transfer in cardiomyocytes.

IKs, the slow component of the delayed rectifier potassium current, figures prominently in the repolarization of heart cells. The K+ channel gene KvLQT1 is mutated in the heritable long QT (LQT) syndrome. Heterologous coexpression of KvLQT1 and the accessory protein minK yields an IKs-like current. Nevertheless, the links between KvLQT1 and cardiac IKs are largely inferential. Since the LQT syndrome mutant KvLQT1-G306R suppresses channel activity when coexpressed with wild-type KvLQT1 in a heterologous system, overexpression of this mutant in cardiomyocytes should reduce or eliminate native IKs if KvLQT1 is indeed the major molecular component of this current. To test this idea, we created the adenovirus AdRMGI-KvLQT1-G306R, which overexpresses KvLQT1-G306R channels. In > 60 % of neonatal mouse myocytes, a sizable IKs could be measured using perforated-patch recordings (8.0 +/- 1.6 pA pF-1, n = 13). IKs was increased by forskolin and blocked by clofilium or indapamide but not by E-4031. While cells infected with a reporter virus expressing only green fluorescent protein (GFP) displayed IKs similar to that in uninfected cells, AdRMGI-KvLQT1-G306R-infected cells showed a significantly reduced IKs (2.4 +/- 1.1 pA pF-1, n = 10, P < 0.01) when measured 60-72 h after infection. Similar results were observed in adult guinea-pig myocytes (5.9 +/- 1.2 pA pF-1, n = 9, for control vs. 0.1 +/- 0.1 pA pF-1, n = 5, for AdRMGI-KvLQT1-G306R-infected cells). We conclude that KvLQT1 is the major molecular component of IKs. Our results further establish a dominant-negative mechanism for the G306R LQT syndrome mutation.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Altered gating of HERG potassium channels by cobalt and lanthanum.

Activation of the rapid, delayed rectifier K current (IKr) is important for normal repolarization of cardiac action potentials, especially in mammalian ventricular muscle. The study of this current has been greatly aided by the discovery that the human ether-a-go-go-related gene (HERG) encodes the pore-forming alpha subunits of these channels. As for other voltage-activated K+ channels, divalent and trivalent cations affect the gating of HERG channels by screening negative membrane surface charges or by direct interaction with the channel gating mechanism. Previous studies have reported that IKr of myocytes, and HERG channels heterologously expressed in Xenopus oocytes, are reduced by external Co2+ and La3+. We have reinvestigated the "blocking" effect of Co2+ and La3+ on HERG channels expressed in Xenopus oocytes. At concentrations previously reported to block IKr or HERG current (IHERG), Co2+ (10 mM) and La3+ (10 microM) had only small effects on the magnitude of fully activated IHERG. The apparent block results from altered kinetics and voltage dependence of gating, similar to the effects of Ca2+ on HERG channels. Under control conditions, the half-points for voltage-dependent activation and inactivation of HERG were -35+/-2.1 and -76.3+/-1.7 mV, respectively. Co2+ and La3+ accelerated the rate of deactivation, decreased the rate of current activation, and shifted the half-point of the HERG channel activation curve by +53 and +65 mV, respectively. Co2+ shifted the voltage dependence of inactivation by + 14 mV, whereas La3+ had no effect. Co2+ also slowed the onset of IHERG inactivation and accelerated the rate of recovery from inactivation. These results indicate that reduction of IHERG by Co2+ (10 mM) and La3+ (10 microM) during depolarizing pulses is caused by a positive shift in the voltage dependence of activation, and does not result from pore block.

Animals↗