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PubMed1997

Appearance of a fast inactivating voltage-dependent K+ currents in developing cerebellar granule cells in vitro.

To elucidate the molecular mechanisms that regulate the maturation of action potential, we began by examining voltage-dependent K+ currents, known to contribute to the maturation of action potential, of developing granule cells in mouse cerebellar microexplant cultures. The migration of developing granule cells in this culture is reported to mimic the in vivo process, but their specific identification is still incomplete. In this study, we identified and characterized granule cells in this culture. Immunocytochemical analysis found that granule cells migrated radially out from explants and subsequently formed small clusters and also that their morphology changed from a bipolar to a T shape during migration. Moreover, in the electrophysiological study, the GABA response of granule cells in this culture clarified that the electrophysiological properties of granule cells were normally maintained. We therefore have concluded, that this culture system is a powerful tool for investigating the differentiation of cerebellar granule cells. Based on these findings, we recorded voltage-dependent K+ currents of developing granule cells in this culture, while concurrently observing their morphology. Our results show that voltage-dependent K+ currents of developing granule cells change from delayed rectifier to A current in parallel with their morphological changes from bipolar to T-shaped cells.

Animals↗
PubMed1999

Potassium currents in developing neurons.

In Xenopus spinal neurons, delayed rectifier type voltage-dependent potassium currents (IKv) are developmentally regulated. These currents play a pivotal role in maturation of the action potential from a long-duration calcium-dependent impulse to a brief sodium-dependent one. Although spinal neurons are heterogeneous, IKv undergoes a synchronized and homogeneous developmental functional up-regulation across this diverse population of motor, sensory, and interneurons. This finding suggested that the diverse population of neurons expressed a common potassium channel. Thus, recent efforts have been directed towards cloning the relevant potassium channel gene. However, these molecular studies reveal an unsuspected heterogeneity in the molecular components of voltage-dependent potassium channels. Further, synchronous differentiation of IKv is achieved via heterogeneous Kv channel gene expression.

Action Potentials↗
PubMed1993

Influence of cloned voltage-gated K+ channel expression on alanine transport, Rb+ uptake, and cell volume.

Voltage-gated K+ channels are involved in regulation of action potential duration and in setting the resting membrane potential in nerve and muscle. To determine the effects of voltage-gated K+ channel expression on processes not associated with electrically excitable cells, we studied cell volume, membrane potential, Na(+)-K(+)-ATPase activity, and alanine transport after the stable expression of the Kv1.4 and Kv1.5 human K+ channels in Ltk- mouse fibroblasts (L-cells). The fast-activating noninactivating Kv1.5 channel, but not the rapidly inactivating Kv1.4 channel, prevented dexamethasone-induced increases in intracellular volume and inhibited Na(+)-K(+)-ATPase activity by 25%, as measured by 86Rb+ uptake. Alanine transport, measured separately by systems A and ASC, was lower in Kv1.5-expressing cells, indicating that the expression of this channel modified the Na(+)-dependent amino acid transport of both systems. Expression of the Kv1.4 channel did not alter alanine transport relative to wild-type or sham-transfected cells. The changes specific to Kv1.5 expression may be related to the resting membrane potential induced by this channel (-30 mV) in contrast to that measured in wild-type sham-transfected, or Kv1.4-transfected cells (-2 to 0 mV). Blocking of the Kv1.5 channel by 60 microM quinidine negated the effects of Kv1.5 expression on intracellular volume, Na(+)-K(+)-ATPase, and Na(+)-dependent alanine transport. These results indicate that delayed rectifier channels such as Kv1.5 can play a key role in the control of cell membrane potential, cell volume, Na(+)-K(+)-ATPase activity, and electrogenic alanine transport across the plasma membrane of electrically unexcitable cells.

Alanine↗
PubMed1995

Electrophysiological and pharmacological characterization of a mammalian Shaw channel expressed in NIH 3T3 fibroblasts.

1. The Shaw-like voltage-activated potassium channel Kv3.1 is expressed in neurons that generate rapid trains of action potentials. By expressing this channel in a mammalian cell line and by simulating its activation, we tested the potential role of this channel in action potential repolarization. 2. NIH 3T3 fibroblasts were stably transfected with Kv3.1 DNA. Currents recorded in these cells had a threshold of activation at approximately -10 mV, showed little inactivation, and were very sensitive to blockade by 4-aminopyridine and tetraethylammonium. 3. Kv3.1 currents activated rapidly at the onset of depolarizing voltage pulses. After an initial rapid phase of activation, which could be fit by an n4 Hodgkin-Huxley model, Kv3.1 currents expressed in fibroblasts had a second, slower phase of activation, and, in some cells, a slower phase of partial inactivation, both of which could be fit with modified n4p models. 4. Cell-attached single-channel recordings indicated that the Kv3.1 channel displays two gating behaviors, a short-open-time pattern, which occurs only at the onset of depolarization, and a long-open-time pattern, which predominates during prolonged depolarizations. 5. The amplitude of Kv3.1 currents, and the probability of channel openings, was reduced by a phorbol ester activator of protein kinase C, and the action of this agent was blocked by preincubation with the protein kinase inhibitor H7 (1-[5-isoquinolinesulfonyl]-2-methyl piperazine). In contrast, the effects of dioctanoyl glycerol, which also attenuated the currents, could not be completely blocked by H7, suggesting that diacylglycerols may act on the channel by a kinase-independent pathway. 6. Incorporation of a current with the kinetics and voltage dependence of Kv3.1 currents into a model cell with a sustained inward current showed that, in contrast to other delayed-rectifier currents such as the Shaker-like Kv1.1 and Kv1.6 channels, the level of expression of Kv3.1 currents could be varied over a wide range without attenuation of action potential height. Our results suggest that the Kv3.1 channel may provide rapidly firing neurons with a high safety factor for impulse propagation.

Action Potentials↗
PubMed1987

Catecholamines modulate the delayed rectifying potassium current (IK) in guinea pig ventricular myocytes.

The effects of isoproterenol and norepinephrine on the delayed, outward potassium current, IK, were tested in single, dialyzed guinea pig heart cells where complications from a restricted extracellular space are minimized and internal K concentration is controlled. The average IK reversal potential in control cells was -80 +/- 2.1 mV (N = 4; [K]o = 4.5 mM; [K]i = 120 mM) indicating a high degree of K selectivity (PNa/PK less than or equal to 0.01). In paired experiments, both isoproterenol and norepinephrine increased IK without changing the reversal potential, indicating that the selectivity of the channels is not altered by these agents. The results explain the shortening of action potential duration observed at high concentrations (Quadbeck and Reiter, 1975); and suggest that an increase in IK by catecholamines may serve to limit the degree of calcium current-induced action potential prolongation during increased sympathetic tone and rapid heart rates.

Action Potentials↗
PubMed1992

Characterization of a delayed rectifier potassium current in chicken growth plate chondrocytes.

With the use of the whole cell arrangement of the patch-clamp technique, an outward-directed time-dependent potassium current was identified in cultured chicken growth plate chondrocytes. This delayed rectifier potassium current (IK) activated with a sigmoidal time course during voltage steps to potentials positive to -40 mV. The half-maximal voltage required for current activation was determined to be -8 mV. The reversal potential (Erev) for IK, measured using deactivating tail currents, was -72 mV in the presence of 140 mM internal and 5 mM external [K+] solutions. Changes in external [K+] caused Erev to shift in a manner expected for a potassium-selective channel. In addition, increasing external [K+] from 5 to 50 mM caused the slope conductance of the tail currents to increase twofold. The chondrocyte IK was inhibited by the potassium-channel blocker 4-aminopyridine (4-AP) at concentrations of 0.5-4 mM and by the scorpion venom toxin charybdotoxin (CTX; 10 nM) but was unaffected by 10 mM tetraethylammonium (TEA). Addition of 20 microM ZnCl2 reduced IK in a voltage-dependent manner with the greatest inhibition found to occur at potentials near the threshold for current activation. Reduction of IK by ZnCl2 was accompanied by a slowing in the kinetics of IK activation. On the basis of the gating and pharmacological properties of this current, it is suggested that the chondrocyte channel belongs to a superfamily of K+ channels found in bone and immune system cells. The chondrocyte K+ channel may contribute to the unusually high [K+] found in the extracellular fluid of growth plate cartilage.

4-Aminopyridine↗
PubMed1994

Voltage-activated potassium currents of rabbit osteoclasts: effects of extracellular calcium.

The effects of increased extracellular Ca2+ concentration ([Ca2+]e) were examined on a delayed-rectifier K+ current (IK) and an inward-rectifier K+ current (IK1) in rabbit osteoclasts. Elevation of [Ca2+]e from 1.8 to 18 mM shifted the half point for IK activation by +11.5 mV and the voltage dependence of inactivation by +9.7 mV and slowed the rate of IK activation and deactivation. These effects of elevated [Ca2+]e on IK are consistent with screening of cell surface negative charge. However, elevation of [Ca2+]e increased the voltage-dependent kinetics of IK inactivation at all potentials tested, inconsistent with that predicted by simple surface charge theory. This finding suggests an additional, regulatory role for [Ca2+]e in the gating of IK channels. Some osteoclasts had an IK1, which was decreased when [Ca2+]e was raised from 1.8 to 18 mM. The physiological function of both types of K+ currents remains to be determined, and it is not clear whether these currents are involved with the coupling of cytosolic [Ca2+] to [Ca2+]e.

Animals↗
PubMed1992

An early outward transient K+ current that depends on a preceding Na+ current and is enhanced by insulin.

A whole-cell early transient outward current occurs in rat myoballs if and only if there is an immediately preceding current of large amplitude through the voltage-gated, tetrodotoxin-inhibitable Na+ channel. This early outward transient is a K+ current, designated IK(Na+). Under the conditions in which IK(Na+) appears, simultaneous measurement of voltage and current, under voltage clamp, demonstrates that there is transient voltage escape to depolarized levels, peaking at about the time of peak inward Na+ current and resembling an action potential. IK(Na+) was never seen in the absence of this breach of the voltage clamp, suggesting that IK(Na+) might be an artefact due to transient depolarization from the clamp. However, when the voltage escape was mimicked by voltage commands under conditions in which the Na+ channel was not activated, there was no IK(Na). Insulin increased or produced IK(Na+) even though insulin had no effect on INa or on the delayed rectifier K+ current or on the escape from voltage clamp. It is concluded that there is a population of rat myoballs in which there is an early outward K+ current that requires an immediately preceding current through the voltage-gated, tetrodotoxin-inhibitable Na+ channel and is enhanced by insulin.

Animals↗
PubMed1987

Pinacidil increases the background potassium current in single ventricular cells.

Pinacidil, a new antihypertensive agent, increased the background (inward rectifier) potassium current and abolished its negative slope, and did not change the time-dependent component of the outward (delayed outward) current in single ventricular cells isolated from the guinea-pig heart. These effects must be responsible for the negative inotropic action of this drug.

Animals↗
PubMed2001

Interaction of azimilide with neurohumoral and channel receptors.

Binding of the class III antiarrhythmic agent azimilide to brain, heart, and other organ receptors was assessed by standard radioligand binding techniques. In a survey of 60 receptors, azimilide at 10 microM inhibited binding by more than 50% at serotonin uptake (K(i): 0.6 microM), muscarinic (K(i): 0.9 to -3.0 microM), Na(+) channel site 2 (K(i): 4.3 microM), and central sigma (K(i): 6.2 microM) sites. Lesser (20-40%) inhibition was seen at adrenergic, histamine, serotonin, purinergic, angiotensin II, dopamine uptake, and norepinephrine sites and at a voltage-sensitive K(+) channel. In rat ventricle, azimilide inhibited binding to alpha(1)- and beta-adrenergic and muscarinic receptors (K(i): < 5 microM) and to the L-type Ca(2+) channel (K(i): 37.3 microM). In rat brain, azimilide blocked ligand binding to these same receptors and to a serotonin receptor, and the breadth and potency of its interaction pattern differentiated it from ten other class III antiarrhythmics. Azimilide displayed agonist and antagonist action at five muscarinic receptor subtypes in transfected NIH 3T3 cells producing receptor-sensitive mitogenesis and beta-galactosidase activity. Agonist action predominated at M(2) and M(4) subtypes, and antagonist action predominated at M(1), M(3), and M(5) subtypes. The azimilide concentration for 50% maximum stimulation (EC(50)) in M(2)-expressing cells was 1.97 microM (vs 0.14 microM for carbachol). Azimilide's receptor interactions occur at concentrations from one to forty times those required to block cardiac delayed-rectifier channels but could contribute to the efficacy and safety of the drug.

Animals↗
PubMed2003

Purification, characterization of two peptides from Buthus martensi Karch.

A new peptide named Martentoxin I and an analogue Martentoxin were purified and characterized from the venom of Buthus martensi Karch. Martentoxin I consisted of 36 amino acid residues with molecular mass as 3908.0 Da determined by matrix-assisted laser desorption ionization time-of-flight-MS. The amino acid sequence was determined as GLIDVKCFASSECWTACKKVTGSGQGKCQNNQCRCY by Edman degradation. Martentoxin consisted of 37 amino acid residues with a molecular mass as 4055.3 Da and it showed highly sequence identity to Martentoxin I as FGLIDVKCFASSECWTACKKVTGSGQGKCQNNQCRCY. Estimation from circular dichroism spectra indicated Martentoxin I owned 18.0% alpha-helix, 53.0% beta-sheet structure and 3.9% turn while Martentoxin contained 13.3% alpha-helix, 64.3% beta-sheet structure and 1.1% turn. The toxicity assay showed both peptides had no toxic effects on mice up to the dose of 10 mg/kg. Electrophysiological studies showed that Martentoxin I and Martentoxin at the concentration of 1 microm significantly inhibited voltage-dependent Na+ current (INa) and voltage-dependent delayed rectifier K+ current (IK) but had no effects on transient K+ current (IA). Both interactions with Na+ and K+ channels were irreversible.

Amino Acid Sequence↗
PubMed1993

Prejunctional action of neostigmine on mouse neuromuscular preparations.

We have studied the effects of neostigmine on the mouse diaphragm and triangularis sterni isolated nerve-muscle preparations. Mechanical responses of the muscle, end-plate potentials and miniature end-plate potentials, and extracellularly recorded nerve ending currents were recorded. In the mouse diaphragm nerve-muscle preparations, neostigmine 1 mumol litre-1 continued to produce some antagonism of tubocurarine-induced block after cholinesterase had been inactivated completely by diisopropyl fluorophosphate 22 mumol litre-1. In the mouse triangularis sterni preparation, neostigmine 0.1-1 mumol litre-1 increased the quantal content of the end-plate potential in a concentration-dependent manner. This effect appeared to be sufficient to account for the cholinesterase-independent antagonistic action to tubocurarine under the conditions of the experiments. Neostigmine 1-100 mumol litre-1 depressed the amplitude of the K+ currents of the perineural waveforms in a concentration-dependent manner, and this may account for its ability to increase the quantal content of the end-plate potential. Although inhibition of acetyl-cholinesterase is the main mechanism of action of neostigmine, the drug also exerts an additional direct action on motor nerve endings to block the delayed rectifier K+ channels and enhance transmitter release. This effect occurred at clinically relevant concentrations of neostigmine. Physostigmine and pyridostigmine did not possess this additional action.

Animals↗
PubMed2000

Effects of amphetamine on calcium and potassium currents in rat heart.

We used the patch-clamp technique to study the effects of amphetamine on the membrane currents responsible for rat cardiac action-potential duration. Amphetamine has no effect on the slow inward Ca2+ current (I(Ca)-L), the inwardly rectifying K+ current (I(K1) and the outward K+ delayed rectifier (I(K)) and sustained (I(SS)) currents. Amphetamine blocks the transient outward K+ current (I(to)) both in the open and in the rested state. The transient outward K+ current is largely responsible for action-potential repolarization and for the regional differences in action-potential duration in rat ventricle. Therefore, the reduction of the transient outward K+ current (I(to)) caused by amphetamine may facilitate the appearance of ventricular tachycardia and fibrillation, a reported cause of death in amphetamine users.

Amphetamine↗
PubMed1990

Transient potassium currents in avian sensory neurons.

1. We used the patch-clamp technique to study voltage-activated transient potassium currents in freshly dispersed and cultured chick dorsal root ganglion (DRG) cells. Whole-cell and cell-attached patch currents were recorded under conditions appropriate for recording potassium currents. 2. In whole-cell experiments, 100-ms depolarizations from normal resting potentials (-50 to -70 mV) elicited sustained outward currents that inactivated over a time scale of seconds. We attribute this behavior to a component of delayed rectifier current. After conditioning hyperpolarizations to potentials negative to -80 mV, depolarizations elicited transient outward current components that inactivated with time constants in the range of 8-26 ms. We attribute this behavior to a transient outward current component. 3. Conditioning hyperpolarizations increased the rate of activation of the net outward current implying that the removal of inactivation of the transient outward current allows it to contribute to early outward current during depolarizations from negative potentials. 4. Transient current was more prominent on the day the cells were dispersed and decreased with time in culture. 5. In cell-attached patches, single channels mediating outward currents were observed that were inactive at resting potentials but were active transiently during depolarizations to potentials positive to -30 mV. The probability of channels being open increased rapidly (peaking within approximately 6 ms) and then declined with a time constant in the range of 13-30 ms. With sodium as the main extracellular cation, single-channel conductances ranged from 18 to 32 pS. With potassium as the main extracellular cation, the single-channel conductance was approximately 43 pS, and the channel current reversed near 0 mV, as expected for a potassium current. 6. We conclude that the transient potassium channels mediate the component of transient outward current seen in the whole-cell experiments. This current is a relatively small component of the net current during depolarizations from normal resting potentials, but it can contribute significant outward current early in depolarizations from hyperpolarized potentials.

Animals↗
PubMed2003

Sodium and potassium clearances by the maturing kidney: clinical-molecular correlates.

A temporal dissociation exists between the early appearance of sodium absorptive and later detection of potassium secretory processes in the maturing rabbit collecting duct. To extend the latter findings to the human, we sought to correlate developmental changes in renal sodium and potassium clearances with the molecular expression of corresponding ion channels in kidneys of premature infants. In a longitudinal prospective study of 23- to 31-week gestational age (GA) infants, sodium, potassium, and creatinine clearances were measured weekly for 5 weeks and the absolute and fractional excretions of sodium (FE(Na)) and potassium (FE(K)) calculated. Gene-specific probes were used to assess steady-state abundance of mRNA encoding the sodium channel ENaC and potassium channel ROMK in homogenates of human kidneys (obtained from the Anatomic Gift Foundation). Although urinary losses of sodium in infants /=28 weeks and all infants >approximately 32 weeks GA achieved a state of positive balance, a maturational process associated with a decrease in FE(Na )and increase in ENaC. Infants >approximately 30 weeks GA maintained a state of positive potassium balance. We noted a twofold reduction in FE(K )after approximately 26 weeks GA and no change in ROMK abundance during the developmental window studied. We speculate that the developmental regulation of renal ENaC expression contributes, at least in part, to the decrease in FE(Na )observed with advancing GA, and that in the human, as in the rabbit, there is a delay between the maturation of sodium absorptive and potassium secretory pathways.

Creatinine↗
PubMed1999

A cell cycle alteration precedes apoptosis of granule cell precursors in the weaver mouse cerebellum.

A missense mutation in the gene coding for the G-protein-activated inwardly rectifying potassium (GIRK) channel, GIRK2, is responsible for apoptosis in the external germinal layer (EGL) of the cerebellum and a nonapoptotic death of midbrain dopaminergic neurons in the weaver (wv) mouse. Failure of axonogenesis and migration are considered to be the primary consequences of GIRK2 channel malfunction in the cerebellum. We investigated whether a disruption of the cell cycle precedes the failure of migration and axonogenesis and leads to massive apoptosis. To this end, immunohistochemistry and immunoblotting for PCNA, Cdk4, cyclin D, cyclin A, and the Cdk inhibitor p27/kip1, as well as in situ end-labeling for apoptotic DNA fragmentation, were applied to cerebella of P7-P21+/+, wv/+, and wv/wv mice. In +/+ and wv/+ mice, the expression of cell cycle proteins was limited to the outer, premigratory zone of the EGL. Antibodies to p27, a marker of cell differentiation, gave a reverse staining pattern. Due to migration delay, patches of p27-positive cells persisted in the outer EGL in P21 wv/+ mice. On the contrary, marked cell cycle up-regulation and absence of p27 occurred throughout the EGL at all ages in wv/wv mice, indicating an inability to switch off the cell cycle. Mitotic index evaluation showed that cell cycle activation was unrelated to proliferative events. Cell cycle proteins were not expressed in the substantia nigra, suggesting that nonapoptotic death of mature dopaminergic neurons is not preceded by abortive cell cycle re-entry. Our data show that abnormalities of the cell cycle in wv/wv cerebellum represent a major and early consequence of GIRK2 channel malfunction and may strongly influence the susceptibility of EGL cells to apoptosis. These observations may help in understanding the pathogenesis of human neurological channelopathies.

Animals↗
PubMed2005

Inwardly rectifying and voltage-gated outward potassium channels exhibit low sensitivity to methylmercury.

The concentration- and time-dependence of effects of methylmercury (MeHg) on voltage-gated outward K(+) (Kv) channels, inwardly rectifying K(+) (Kir) channels, voltage-gated Ca(2+) channels and GABA(A) receptor activated channels were compared in cerebellar granule cells in culture using whole cell patch clamp recording techniques. The objective was to determine if MeHg equally affects different types of ion channels. Under similar experimental conditions, these four ion channel types displayed markedly different sensitivity to MeHg. At 0.1-1 microM, MeHg caused apparent inhibition of Ca(2+)-channel and GABA(A) receptor-mediated currents, but did not cause any significant effect on Kv or Kir channels. Among the four channel types examined, GABA(A) receptors appeared to be the most sensitive to MeHg. The Kv channels, particularly the delayed rectifiers (DRs), appeared to be relatively resistant to MeHg compared with GABA(A) receptors and Ca(2+) channels. Kir channels were virtually unaffected by MeHg in the concentration range of 10-100 microM. The differential sensitivity of GABA(A) receptors and Kv channels to MeHg was also observed in granule and Purkinje cells in freshly isolated cerebellar slices of rat. The insensitivity of Kir channel to MeHg was also seen in Xenopus laevis oocytes expressing cloned Kir7.1 channels. Thus, these appear to be general properties of these channels as opposed to distinct effects associated with granule cells in culture. These results suggest that MeHg does preferentially affect certain types of ion channels. Hence, the effects of MeHg on membrane ion channels are not due simply to nonspecific actions on the membrane. Furthermore, at least certain types of Kir channels appear to be the most resistant type of ion channel reported to date to effects of MeHg.

Animals↗
PubMed1995

Multiple components of delayed rectifier K+ current in canine colonic smooth muscle.

1. We investigated the pharmacology and voltage-dependent activation and inactivation kinetics of the 'delayed rectifier' K+ current, IdK, in canine colonic myocytes and developed protocols which separate this current into three distinct components that differ in their kinetics and pharmacology. 2. Block of IdK by TEA or 4-aminopyridine (4-AP) alone was incomplete. Maximal concentrations of TEA or 4-AP blocked 76% (EC50 = 2.6 mM) and 51% (EC50 = 69 mM) of current, respectively. In the presence of 10 mM 4-AP, IdK could be blocked completely by TEA. 3. TEA and 4-AP had distinct effects on current activation: time constants for activation of IdK at +10 mV were 25.6 +/- 4.4 ms under control conditions, 40.3 +/- 7.6 ms in the presence of 10 mM 4-AP and 16.7 +/- 2.3 ms with 10 mM TEA in the bath solution. 4-AP block and removal of block were use dependent, but no frequency dependence or voltage dependence of steady-state block could be detected. These data are consistent with the presence of a rapidly activating 4-AP-sensitive current, IdK(f), and a more slowly activating TEA-sensitive current component, IdK(s). 4. A third component of the delayed rectifier current, IdK(n), was revealed when 10 mM TEA was included in the pipette solution. IdK(n) was rapidly activating, had a membrane potential at half-maximal inactivation (V1/2) for steady-state inactivation 13 mV negative of that for the mixed IdK, was completely insensitive to 4-AP (10 mM) and was blocked by external TEA with an EC50 of 7.7 mM. 5. These data demonstrate that the delayed rectifier current in canine colonic smooth muscle is composed of three currents, IdK(f), IdK(s) and IdK(n). All three currents are insensitive to charybdotoxin (100 nM).

4-Aminopyridine↗