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Results for “Delayed Rectifier Potassium Channels”

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PubMed2003

One scorpion, two venoms: prevenom of Parabuthus transvaalicus acts as an alternative type of venom with distinct mechanism of action.

Scorpion venom is a complex mixture of salts, small molecules, peptides, and proteins. Scorpions employ this valuable tool in several sophisticated ways for subduing prey, deterring predators, and possibly during mating. Here, a subtle but clever strategy of venom utilization by scorpions is reported. Scorpions secrete a small quantity of transparent venom when initially stimulated that we propose to name prevenom. If secretion continues, a cloudy and dense venom that is white in color is subsequently released. The prevenom contains a combination of high K(+) salt and several peptides including some that block rectifying K(+) channels and elicit significant pain and toxicity because of a massive local depolarization. The presence of high extracellular K(+) in the prevenom can depolarize cells and also decrease the local electrochemical gradient making it more difficult to reestablish the resting potential. When this positive change to the K(+) equilibrium potential is combined with the blockage of rectifying K(+) channels, this further delays the recovery of the resting potential, causing a prolonged effect. We propose that the prevenom of scorpions is used as a highly efficacious predator deterrent and for immobilizing small prey while conserving metabolically expensive venom until a certain level of stimuli is reached, after which the venom is secreted.

Animals↗
PubMed1997

Hypoxia inhibits gene expression of voltage-gated K+ channel alpha subunits in pulmonary artery smooth muscle cells.

Activity of voltage-gated K+ channels (KV) in pulmonary arterial smooth muscle cells (PASMC) is pivotal in controlling membrane potential, cytoplasmic free Ca2+ concentration ([Ca2+]cyt, and pulmonary vasomotor tone. Acute hypoxia selectively inhibits KV channels, depolarizes PASMC, raises [Ca2+]cyt, and causes pulmonary vasoconstriction and vascular remodeling. Prolonged hypoxia (24-60 h) decreased significantly the mRNA levels of KV channel alpha subunits, KV1.2 and KV1.5. Consistently, the protein levels of KV1.2 and KV1.5 were also decreased significantly by hypoxia (48-72 h). Nevertheless, hypoxia affected negligibly the mRNA levels of KV channel beta subunits (KVbeta1, KVbeta2, and KVbeta3). The native K+ channels are composed of pore-forming alpha and auxiliary beta subunits. Assembly of KV beta subunits with alpha subunits confers rapid inactivation on the slowly or non-inactivating delayed rectifier KV channels. KV beta subunits also function as an open-channel blocker of KV channels. Thus, the diminished transcription and expression of KV alpha subunits may reduce the number of KV channels and decrease KC currents. Unchanged transcription of KV beta subunits may increase the fraction of the KV channel alpha subunits that are associated with beta subunits and further reduce the total KV currents. These data demonstrate a novel mechanism by which chronic hypoxia may cause pulmonary vasoconstriction and hypertension.

Animals↗
PubMed1992

Cloning and modulation by endothelin-1 of rat cardiac K channel.

We have cloned a delayed rectifier type K channel from rat heart (RH1). RH1 was identical to the rat brain K channel BK2 and differed from recently cloned rat cardiac K channel RAK by one amino acid residue. Endothelin receptors(ETRs)-mediated modulation of RH1 current (IRH1) was studied using Xenopus oocyte expression system. Activation of two different subtypes of ETRs by endothelin-1 equally suppressed the amplitude of IRH1. Stimulation of phosphatidylinositol turnover will probably be responsible for the suppression.

Animals↗
PubMed2003

The electrophysiological properties of spontaneously beating pacemaker cells isolated from mouse sinoatrial node.

In order to examine the phenotypic consequences of genetic manipulation in the function of the sinoatrial (SA) node, it is a prerequisite to record the electrical activities of a single pacemaker cell of the SA node of mouse heart. In the present study, we isolated spontaneously beating pacemaker cells from the SA node by enzymatic digestion. The rate of spontaneous action potential firing was 294 + 59 min-1 at 33-34 degrees C. The maximal diastolic potential (MDP) was -56.7 +/- 7.4 mV and the overshoot was 22.7 +/- 6.2 mV. With hyperpolarizing voltage clamp pulses, the hyperpolarization-activated, cyclic nucleotide-sensitive cation current (I(h) or I(f)) was recorded. lb started to activate at-70 to approximately -80 mV, more negative than MDP. The half-maximal activation of Ih was obtained at -107.9 +/- 10.4 mV. The inward-rectifier K+ current (IK1) was also recorded in spontaneously beating myocytes. However, the amplitude of outward IK1 was negligibly small (9.1 +/- 3.4 pA at -60 mV). With depolarization, voltage-gated Na+ current, L-type Ca2+ current and T-type Ca2+ current were consistently observed. The sustained inward current (I(st)) was also recorded in spontaneously beating pacemaker cells. E4031-sensitive, rapidly activating delayed rectifier K+ current (I(Kr)) was activated by depolarization, although the amplitude was no more than 38.3 +/- 22.2 pA at 0 mV. The chromanol 293B-sensitive, slowly activating delayed rectifier K+ current (I(Ks)) was not present. The major repolarizing current was the slowly inactivating, 4-aminopyridine-insensitive outward current. We concluded that mouse pacemaker cells possess similar membrane currents, including I(st), to those of other species.

Action Potentials↗
PubMed1997

Does tyrosine kinase modulate delayed-rectifier K channels in guinea pig ventricular cells?

Phosphorylation by tyrosine kinases has been shown to promote cellular growth and hypertrophy and to play a key role in modulating ion channels. We have examined possible effects of genistein, a protein tyrosine kinase (PTK) inhibitor, on cardiac delayed-rectifier K currents (IK). Guinea pig ventricular myocytes were voltage-clamped by conventional whole-cell mode (5.4 mM [K]out/150 mM [K]in; pCa = 8; 36 degrees C). Amplitudes of tail and steady-state (2-s pulse) currents were measured as IK. Micromolar concentrations of genistein (10-100 microM) reversibly inhibited basal, swelling-enhanced (by 70% hypotonic solution), and intrapipette Cyclic adenosine monophosphate (cAMP) (1 mM)-enhanced IK concentration-dependently, while intrapipette cAMP-enhanced IK were also affected by daidzein, an inactive analog of genistein. In contrast, lavendustin A (10 microM) and tyrphostin 51 (100 microM), other types of PTK inhibitors, had no effect on IK. These results suggest that genistein may inhibit IK and that this inhibition is not mediated by an inhibition of tyrosine kinase activity.

Animals↗
PubMed1998

Uneven distribution of K+ channels in soma, axon and dendrites of rat spinal neurones: functional role of the soma in generation of action potentials.

1. A novel method of 'entire soma isolation' was used to describe the distribution of voltage-gated K+ channels between soma, axon and dendrites of dorsal horn neurones identified in spinal cord slices of newborn rat. 2. The soma contained 36 % of total inactivating (KA) current but only 15 % of delayed rectifier (KDR) current. The axon initial segment possessed almost half (47 %) of the total KA current and 38 % of KDR current. In contrast, dendrites contained a small portion (17 %) of KA but 47 % of KDR current. 3. Under current-clamp conditions, the soma isolated from axon and dendrites was not able to generate action potentials. It passively conducted weak (</= -50 mV) and amplified pronounced (-50 to 0 mV) depolarizations but inhibited strong (>/= 0 mV) depolarizations. 4. It is concluded that the soma plays a complex role in the excitability of spinal dorsal horn neurones. It conducts passively or amplifies excitatory postsynaptic potentials on their way from dendrites and soma to the axon initial segment but it inhibits back-propagation of the action potential from the axon to the dendrites.

4-Aminopyridine↗
PubMed1995

Two voltage-dependent K+ conductances with complementary functions in postsynaptic integration at a central auditory synapse.

The medial nucleus of the trapezoid body (MNTB) relays auditory information important for sound source localization. MNTB neurons faithfully preserve the temporal patterning of action potentials (APs) occurring in their single giant input synapse, even at high frequencies. The aim of this work was to examine the postsynaptic potassium conductances that shape the transfer of auditory information across this glutamatergic synapse. We used whole cell patch techniques to record from MNTB neurons in thin slices of rat brainstem. Two types of potassium conductance were found which had a strong influence on an MNTB neuron's postsynaptic response. A small low voltage threshold current, Id, limited the response during each EPSP to a single brief AP. Id was specifically blocked by dendrotoxin (DTX), resulting in additional APs during the tail end of the EPSP. Thus DTX degraded the temporal fidelity of synaptic transmission, since one presynaptic AP then led to several postsynaptic APs. A second conductance was a fast delayed rectifier with a high voltage activation threshold, that rapidly repolarised APs and thus facilitated high frequency AP responses. Together, these two conductances allow high frequency auditory information to be passed accurately across the MNTB relay synapse and separately, such conductances may perform analogous functions elsewhere in the nervous system.

Animals↗
PubMed2001

Electrophysiological characteristics of reactive astrocytes in experimental cortical dysplasia.

Neocortical freeze lesions have been widely used to study neuronal mechanisms underlying hyperexcitability in dysplastic cortex. Comparatively little attention has been given to biophysical changes in the surrounding astrocytes that show profound morphological and biochemical alterations, often referred to as reactive gliosis. Astrocytes are thought to aid normal neuronal function by buffering extracellular K(+). Compromised astrocytic K(+) buffering has been proposed to contribute to neuronal dysfunction. Astrocytic K(+) buffering is mediated, partially, by the activity of inwardly rectifying K(+) channels (K(IR)) and may involve intracellular redistribution of K(+) through gap-junctions. We characterized K(+) channel expression and gap-junction coupling between astrocytes in freeze-lesion-induced dysplastic neocortex. Whole cell patch-clamp recordings were obtained from astrocytes in slices from postnatal day (P) 16--P24 rats that had received a freeze-lesion on P1. A marked increase in glial fibrillary acidic protein immunoreactivity was observed along the entire length of the freeze lesion. Clusters of proliferative (bromo-deoxyuridine nuclear staining, BrdU+) astrocytes were seen near the depth of the microsulcus. Astrocytes in cortical layer I surrounding the lesion were characterized by a significant reduction in K(IR). BrdU-positive astrocytes near the depth of the microsulcus showed essentially no expression of K(IR) channels but markedly enhanced expression of delayed rectifier K(+) (K(DR)) channels. These proliferative cells showed virtually no dye coupling, whereas astrocytes in the hyperexcitable zone adjacent to the microsulcus displayed prominent dye-coupling as well as large K(IR) and outward K(+) currents. These findings suggest that reactive gliosis is accompanied by a loss of K(IR) currents and reduced gap junction coupling, which in turn suggests a compromised K(+) buffering capacity.

Animals↗
PubMed1996

Tissue extract from dopamine-depleted striatum enhances differentiation of cultured striatal type-1 astrocytes.

The effects of tissue extract from dopamine (DA)-depleted striatum (lesion extract, L-ext) on morphological and electrophysiological natures of cultured striatal astrocytes were investigated. L-ext treatment suppressed the proliferation of type-1 astrocytes. They became fibrous in a concentration-dependent manner. These changes were not observed in type-2 astrocytes. By whole cell patch-clamp recording, two kinetically and pharmacologically distinct voltage-activated potassium currents, A current and delayed rectifier, were identified. L-ext treatment enhanced both currents in type-1 astrocytes, but only A current in type-2. Data suggest that in tissue extract from DA-depleted striatum, there are increased trophic activities that promote the differentiation of type-1 astrocytes.

Animals↗
PubMed1995

Use-dependent effects of the class III antiarrhythmic agent NE-10064 (azimilide) on cardiac repolarization: block of delayed rectifier potassium and L-type calcium currents.

We studied the effects of NE-10064 (azimilide), a new antiarrhythmic agent reported to be a selective blocker of the slowly activating component of the delayed rectifier, IKs. In ferret papillary muscles, NE-10064 increased effective refractory period (ERP) and decreased isometric twitch tension in a concentration-dependent manner (0.3-30 microM). Increases in ERP showed reverse use-dependence, and were greater at 1 than at 3 Hz. In contrast, changes in tension were use dependent, with larger decreases observed at 3 than at 1 Hz. In guinea pig ventricular myocytes, NE-10064 (0.3-3 microM) significantly prolonged action potential duration (APD) at 1 Hz. At 3 Hz, NE-10064 (0.3-1 microM) increased APD only slightly, and at 10 microM decreased APD and the plateau potential. NE-10064 potently blocked the rapidly activating component of the delayed rectifier, IKr (IC50 0.4 microM), and inhibited IKs (IC50 3 microM) with nearly 10-fold less potency. NE-10064 (10 microM) did not block the inward rectifier potassium current (IKl). NE-10064 (10 microM) blocked the L-type calcium current (ICa) in a use-dependent manner; block was greater at 3 than at 1 Hz. We conclude that (a) NE-10064's block of potassium currents is relatively selective for IKr over IKs, (b) NE-10064 inhibits ICa in a use-dependent fashion, and (c) NE-10064's effects on ERP and tension in papillary muscle as well as APD and action potential plateau level in myocytes may be explained by its potassium and calcium channel blocking properties.

Action Potentials↗
PubMed2002

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts.

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K(+) current (I(K1)) was homogeneously reduced by approximately 41% (at -60 mV) in the three cell types. Transient outward K(+) current (I(to1)) was decreased by 43-45% at +30 mV, and the slow component of the delayed rectifier K(+) current (I(Ks)) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K(+) current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I(K1), I(to1), and I(Ks) increases APD and favors occurrence of EADs.

Action Potentials↗
PubMed2001

HERG K+ channels: friend and foe.

The K+ channel encoded by the human ether-à-go-go related gene (HERG) is one of many ion channels that are crucial for normal action potential repolarization in cardiac myocytes. HERG encodes the pore-forming subunit of the rapid component of the delayed rectifier K+ channel, I(K(Vr)). HERG K+ channels are of considerable pharmaceutical interest as possible therapeutic targets for anti-arrhythmic agents and as the molecular target responsible for the cardiac toxicity of a wide range of pharmaceutical agents. Recent studies of the molecular basis of the promiscuity of HERG K+ channel drug binding has not only started to shed light on this tricky pharmaceutical problem but has also provided further insights into the structure and function of HERG K+ channels.

Animals↗
PubMedDate not supplied

Identified ion channels in the squid nervous system.

Our modern understanding of channels as discrete voltage-sensitive and ion-selective entities comes largely from a series of classical studies using the squid giant axon. This system has also been critical for understanding how transporters and synaptic transmission operate. This review outlines attempts to assign molecular identities to the extensively studied physiological properties of this system. As it turns out, this is no simple task. Molecular candidates for voltage-gated Na(+), K(+), and Ca(2+) channels, as well as ion transporters have been isolated from the squid nervous system. Both physiological and molecular approaches have been used to equate these cloned gene products with their native counterparts. In the case of the delayed rectifier K(+) conductance, the most thoroughly studied example, two major issues further complicate the equation. First, the ability of K(+) channel monomers to form heteromultimers with unique properties must be considered. Second, squid K(+) channel mRNAs are extensively edited, a process that can generate a wide variety of channel proteins from a common gene. The giant axon system is beginning to play an important role in understanding the biological relevance of this latter process.

Animals↗
PubMed2005

Open-state unblock characterizes acute inhibition of I potassium current by amiodarone in guinea pig ventricular myocytes.

INTRODUCTION: The aim of the present study was to investigate the acute action of amiodarone on the slow component of delayed rectifier K+ current (IKs) under basal conditions and during beta-adrenoceptor stimulation in guinea pig ventricular myocytes. METHODS AND RESULTS: Using the whole-cell patch-clamp method, IKs was evoked by depolarizing voltage-clamp steps, during superfusion with the Na+-, K+-, and Ca2+-free solution supplemented with 0.4 microM nisoldipine and 5 microM E-4031. The acute effect of amiodarone was evaluated, within approximately 10 minutes after starting the bath application, by the amplitude of deactivating tail currents at -50 mV. Amiodarone concentration dependently blocked I(Ks) and exerted a more potent effect on IKs when activated by shorter pulse durations; the degree of block by 30 microM amiodarone on IKs activated by 200 ms, 500 ms, and 2000 ms depolarizing pulses to +30 mV was 55.9 +/- 5.8%, 38.6 +/- 6.0%, and 27.1 +/- 4.0% (n = 5 each), respectively. An envelope of tails test conducted at +10, +30, and +60 mV demonstrated that the degree of IKs block by amiodarone was gradually attenuated during membrane depolarization, which can be described by a monoexponential function, thus supporting the presence of open channel unblock. Amiodarone also blocked IKs maximally stimulated by 1 microM isoprenaline, to an extent similar to control, when IKs was activated by pulse durations of < or =2000 ms. CONCLUSION: We propose that amiodarone acutely blocks native IKs with characteristics associated with open channel unblock, and that the protein kinase A-mediated phosphorylation of channel proteins only minimally affects the amiodarone block.

AMP-Activated Protein Kinases↗
PubMed1995

[Ca2+]i inhibition of K+ channels in canine pulmonary artery. Novel mechanism for hypoxia-induced membrane depolarization.

Experiments were performed on smooth muscle cells isolated from canine pulmonary artery to identify the type of K+ channel modulated by hypoxia and examine the possible role of [Ca2+]i in hypoxic K+ channel inhibition. Whole-cell patch-clamp experiments revealed that hypoxia (induced by the O2 scavenger, sodium dithionite) reduced macroscopic K+ currents, an effect that could be prevented by strong intracellular buffering of [Ca2+]i. The inhibitory effects of hypoxia were mimicked by acute exposure of cells to caffeine and could be prevented by caffeine pretreatment, suggesting an important obligatory role of [Ca2+]i in hypoxic inhibition of K+ currents. Exposure of cells to low concentrations of 4-aminopyridine (4-AP, 1 mmol/L) prevented hypoxic inhibition of macroscopic K+ currents, whereas low concentrations of tetraethylammonium were without effect, suggesting that the target K+ channel inhibited by hypoxia is a voltage-dependent delayed rectifier K+ channel, which is inhibited by [Ca2+]i. Hypoxia failed to consistently modify the activity of large-conductance (118 picosiemens [pS] in physiological K+) Ca(2+)-activated K+ channels in inside-out membrane patches but reduced open probability of smaller-conductance (25-pS) delayed rectifier K+ channels in cell-attached membrane patches. In inside-out membrane patches, 1 mumol/L Ca2+ added to the cytoplasmic surface significantly reduced open probability of small-conductance (25-pS) 4-AP-sensitive delayed rectifier K+ channels. Whole-cell current measurements using symmetrical K+ to increase driving force for small currents active near the cell's resting membrane potential revealed the presence of a 4-AP-sensitive K+ current that activated near -65 mV and was inhibited by hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed2005

Kv2.1: a voltage-gated k+ channel critical to dynamic control of neuronal excitability.

Neurons use a variety of mechanisms to dynamically control their own signaling capabilities. Regulation of voltage-dependent K+ channel localization and function has long been recognized as a major mechanism to achieve dynamic regulation of intrinsic neuronal excitability in a number of mammalian and non-mammalian neurons. Our recent evidence, together with compelling data from other laboratories, suggests that in mammalian neurons the Kv2.1 channel may play an especially prominent role in determining intrinsic neuronal excitability. Kv2.1 is widely expressed in brain and composes the majority of delayed rectifier K+ current in pyramidal neurons in cortex and hippocampus, and is also widely expressed in interneurons. Dynamic modulation of Kv2.1 localization and function by a mechanism involving activity-dependent Kv2.1 dephosphorylation dramatically impacts intrinsic excitability of neurons. Here we review previous studies of Kv2.1 localization and function in neurons, and summarize recent work regarding dynamic regulation of these characteristics. We also discuss possible roles of the Kv2.1 channel in neuronal and network excitability.

Animals↗
PubMed2001

Inhibition of cardiac delayed rectifier K+ currents by an antisense oligodeoxynucleotide against IsK (minK) and over-expression of IsK mutant D77N in neonatal mouse hearts.

The IsK (minK or KCNE1) protein is known to co-assemble with the KvLQT1 (KCNQ1) protein to form a channel underlying the slowly activating delayed rectifier K+ current (IKs). Controversy remains as to whether the IsK protein assembles with ERG (the ether-a-go-go-related gene) products to form or modulate the channel-underlying the rapidly activating delayed rectifier K+ current (IKr). We investigated the effects of antisense oligodeoxynucleotides (AS-ODN) against IsK and its mutant D77N [which underlies a form of long QT syndrome (LQT5) in humans] on the delayed rectifier K+ current (IK) of neonatal mouse ventricular myocytes in primary culture. Patch-clamp experiments on these cells showed that IK consists of IKs and IKr. IK was not recorded from ventricular cells transfected with AS-ODN, while it was recorded from cells transfected with the corresponding sense oligodeoxynucleotides (S-ODN). IK was not recorded from cells transfected with the D77N mutant, and the action potential duration was much longer than in cells transfected with wild-type IsK. Furthermore, HERG could not induce currents in COS-1 cells co-expressed with the D77N mutant and HERG (the human form of ERG). These results indicate that the IsK protein associates with both KvLQT1 and ERG products to modulate IKr and IKs in cardiac myocytes.

Action Potentials↗
PubMed2002

Antioscillatory effects of nociceptin/orphanin FQ in synaptic networks of the rat thalamus.

Postsynaptic and presynaptic effects of nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor, were investigated in an in vitro slice preparation of the rat thalamic reticular nucleus (NRT) and ventrobasal complex (VB). In NRT as well as VB, all tested neurons developed an outward current on application of 1 micrometer N/OFQ. Basic properties of the N/OFQ-induced current included inward rectification, dependence on extracellular K(+), reduction by 100 micrometer Ba(+), antagonistic effect of [Nphe(1)]nociceptin(1-13)NH(2), and sensitivity to internal GDP-beta-S. Miniature IPSCs (mIPSCs) mediated by GABA(A) receptors in VB neurons were not affected by 1 micrometer N/OFQ. In addition, paired-pulse depression of evoked IPSCs was unchanged, indicating a lack of presynaptic effects. By comparison, N/OFQ application resulted in a reduction in frequency of miniature EPSCs (mEPSCs) in a subpopulation of NRT neurons, whereas paired-pulse facilitation of evoked EPSCs was not altered. In either nucleus, current-clamp experiments revealed a hyperpolarization and associated decrease in input resistance in response to N/OFQ. Although N/OFQ had no measurable effect on calcium-mediated burst activity evoked by depolarizing steps from hyperpolarized values of the membrane potential, rebound bursts on relief of hyperpolarizing current steps were decreased. Slow thalamic oscillations induced in vitro by extracellular stimulation were dampened by N/OFQ in VB and NRT, as seen by delayed onset of rhythmic multiple-unit activity and reduction in amplitude and duration. We conclude that N/OFQ reduces the excitability of NRT and VB neurons predominantly through an increase of a G-protein-coupled inwardly rectifying K(+) conductance.

Animals↗