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PubMed1993

Mitogenic factors regulate ion channels in Schwann cells cultured from newborn rat sciatic nerve.

1. Patch clamp studies were carried out in Schwann cells cultured from newborn rat sciatic nerve to determine the effects of mitogens on voltage-gated currents without the confounding influences of axonal contact and myelin present in vivo. The relevance of the various Schwann cell currents to proliferation was assessed using assays of [3H]thymidine incorporation. 2. Treatment of cultured Schwann cells with known mitogens, namely axon fragments (AF), myelin fragments (MF), or glial growth factor in combination with forskolin (GGF+F), increased the magnitudes of delayed rectifying potassium (K+) and sodium (Na+) currents. 3. In both control and mitogen-treated cells, the magnitude of net outward current paralleled clearly the magnitude of the cells' proliferative response. 4. The K+ channel-blocking quaternary ammonium ions, tetrabutylammonium (TBuA), tetrapentylammonium (TPeA) and tetrahexylammonium (THeA), but not the Na+ channel blocker tetrodotoxin (TTX), reduced proliferation in a dose-dependent fashion offering further evidence for a role for K+ channels in Schwann cell proliferation. 5. Voltage-gated chloride (Cl-) currents were observed in both control and mitogen-treated cells. Addition of the Cl- channel blockers, 4-acetamido-4'-isocyanatostilbene-2,2'-disulphonate (SITS) or 4,4'-diisothiocyanatostilbene-2,2'-disulphonate (DIDS), to the culture media enhanced proliferation. 6. The possible intermediary role of the Schwann cell resting potential was explored in ion substitution experiments by increasing the K+ concentration of the media and by adding ouabain. Both manipulations inhibited Schwann cell mitosis. 7. Comparison of the expression of functional ion channels in vitro with that previously described for Schwann cells in vivo suggests a difference in the Schwann cell response to the membrane fragment mitogens and their intact counterparts in regard to the regulation of ion channels. MF up-regulates the number of functional channels, whereas the elaboration of myelin (or a factor related to its presence) in vivo appears to down-regulate channel expression, at the cell soma of myelinating Schwann cells. In addition, axonal contact may be required for normal expression of functional inwardly rectifying K+ channels.

Animals↗
PubMed1993

Potassium channel blocking properties of propafenone in rabbit atrial myocytes.

Propafenone, a class 1c antiarrhythmic agent, is known to be a potent blocker of voltage-dependent sodium channels; however, several clinical actions of the drug point toward possible potassium channel blocking capability. The present experiments were designed to assess the extent and potential mechanisms of potassium channel blocking properties of propafenone. Whole-cell voltage-clamp techniques were used to define the actions of propafenone on the transient outward current (Ito), the delayed rectifier current (Ik) and the inward rectifier current (Ik1) in isolated rabbit atrial myocytes. Propafenone blocked all three currents, with the extent of blockade being independent of test potential During depolarizing voltage steps, block of Ito and Ik developed as an exponential function of time, consistent with time-dependent open channel blockade. The rate constant of block onset was concentration dependent. The inactivation of Ito was a monoexponential function of time under control conditions, with a time constant averaging 19.1 +/- 1.3 msec (mean +/- S.E.) at +10 mV. Propafenone accelerated Ito inactivation, resulting in a biexponential process having time constants of 5.1 +/- 0.9 (P < .001 vs. control) and 23.5 +/- 2.0 msec (P = N.S. vs. control) at 5 microM and 3.4 +/- 0.5 (P < .001 vs. control) and 28.5 +/- 4.3 msec (P = N.S.) at 10 microM concentrations, respectively. The rapid phase inactivation time constants were of the same order as time constants for the onset of block (3.1 +/- 0.6 and 1.8 +/- 0.3 msec at 5 and 10 microM respectively), suggesting that the acceleration of Ito inactivation was due to open channel block by the drug. The IC50 for blockade was substantially less for effects on Ik (0.76 microM; 95% confidence limits 0.44-1.30 microM) than for Ito (5.91 microM; 95% confidence limits 4.19-8.33 microM) or Ik1 (7.10; 5.24-9.61 microM). We conclude that 1) propafenone is an efficacious potassium channel blocker; 2) propafenone blockade of time-dependent potassium currents is open-state dependent; and 3) propafenone block of potassium currents is relatively selective for Ik.

Animals↗
PubMed1995

The role of potassium channels in excitable cells.

Potassium (K) channels regulate cellular excitability. Their opening hyperpolarises the membrane potential and induces quiescence whereas their closure produces depolarisation and excitation. One K-channel superfamily includes the delayed rectifier (KV), the A-type (KA) and the large conductance, Ca-sensitive (BKCa) channels. These serve to terminate excitatory events and consist of a tetramer of alpha-subunits each comprising six transmembrane-spanning segments including a voltage-sensor. Additional beta-subunits which modify inactivation and voltage sensitivity may also be present. Channels in the second superfamily include the inward rectifiers (KIR) and the ATP-sensitive K-channel (KATP). Their tetrameric assembly of alpha-subunits contains only two transmembrane-spanning segments and lacks a voltage sensor. KATP is associated with a sulphonylurea binding site belonging to the ATP-binding cassette family. Although KIR conducts poorly at potentials positive to EK, both it and KATP do conduct over the physiological potential range. K-channel modulators are important in determining channel function. These include drugs like tetraethylammonium and 4-aminopyridine and more recently-discovered selective agents active at KATP and BKCa. These are typified by diazoxide, levcromakalim and glibenclamide and by NS1619, iberiotoxin and penitrem A, respectively.

Animals↗
PubMed1995

Effects of insulin on potassium currents of rat ventricular myocytes in streptozotocin diabetes.

Membrane currents of ventricular cardiomyocytes isolated from control, diabetic and insulin-treated diabetic Wistar rats have been measured using the whole cell configuration of the patch-clamp technique. Insulin restored the density of the 4-aminopyridine-sensitive early transient component of the calcium-independent outward potassium currents which decreased in diabetes. The inactivation rate of the transients increased in diabetes and was normalised by insulin. The late 4-aminopyridine-insensitive component of the outward currents showed the same diabetes- and insulin-related changes. This current could reflect the activation of the delayed rectifier channels although pharmacological identification of this component could not be achieved.

4-Aminopyridine↗
PubMed1989

The Ca2+-activated K+ channel and its functional roles in smooth muscle cells of guinea pig taenia coli.

Currents through single potassium channels were studied in cell-attached or inside-out patches from collagenase-dispersed smooth muscle cells of the guinea pig taenia coli. Under conditions mimicking the physiological state with [K+]i = 135 mM: [K+]o = 5.4 mM, three distinct types of K+ channel were identified with conductances around 0 mV of 147, 94, and 63 pS. The activities of the 94- and 63-pS channel were observed infrequently. The 147-pS channel was most abundant. It has a reversal potential of approximately -75 mV. It is sensitive to [Ca2+]i and to membrane potential. At -30 mV, the probability of a channel being open is at a minimum. At more positive voltages, the probability follows Boltzman distribution. A 10-fold change in [Ca2+]i causes a 25-mV negative shift of the voltage where half of the channels are open; an 11.3-mV change in membrane potential produces an e-fold increase in the probability of the channel being open when P is low. At voltages between -30 and -50 mV, the open probability increases in an anomalous manner because of a large decrease of the channel closed time without much change in the channel open time. This anomalous activity may play a regulatory role in maintaining the resting potential. The histograms of channel open and closed time fit well, respectively, with single and double exponential distributions. Upon step depolarizations by 100-ms pulses, the 147-pS channel opens with a brief delay. The delay shortens and both the number of open channels and the open time increase with increasing positivity of the potential. The averaged currents during the step depolarizations closely resemble the delayed rectifying outward K+ currents in whole-cell recordings.

Animals↗
PubMed2002

FMRFamide modulates potassium currents in circadian pacemaker neurons of Bulla gouldiana.

The peptide FMRFamide (Phe-Met-Arg-Phe-NH(2)) is known to modulate the circadian pacemaker found in the eye of the marine snail Bulla gouldiana. In the present study, we investigated the cellular mechanisms underlying this modulation by examining the effects of FMRFamide on the membrane properties of the circadian pacemaker cells, known as basal retinal neurons in this preparation. Bath application of FMRFamide (0.1-1 microM) increased the membrane conductance, and hyperpolarized the membrane potential of these neurons. Next, perforated-patch recordings were used to demonstrate that FMRFamide reversibly increased the outward current amplitude due to an augmentation of a non-inactivating calcium-independent current. Reversal potential of the tail currents and its dependence on extracellular potassium concentration suggested potassium ions as the charge carrier for this current. The peptide-modulated outward current was blocked by 54% after bath application of the potassium channel blocker tetraethylammonium chloride and completely blocked by substituting cesium for intracellular potassium. Voltage dependence, activation kinetics and tail current kinetics of the FMRFamide-modulated current were consistent with values found for the delayed rectifier current.Overall, our data suggest that FMRFamide modulates a delayed rectifier potassium current and at least one other, less voltage-dependent conductance. This provides a mechanistic explanation for FMRFamide's ability to both shift the phase and attenuate light-induced phase shifts of the circadian pacemaker in B. gouldiana.

Action Potentials↗
PubMed1993

Conductances contributing to the action potential of Sternopygus electrocytes.

In Sternopygus macrurus, electrocyte action potential duration determines the electric organ discharge pulse duration. Since the electric organ discharge is a sexually-dimorphic behavior under the control of steroid hormones, and because electrocyte action potential durations can range from 3-14 ms, the electrocytes provide a unique opportunity to study how sex steroids regulate membrane excitability. In this study, the voltage-sensitive ionic currents of electrocytes were identified under current- and voltage-clamp as a prelude to further studies on their regulation by sex steroid hormones. Bath application of TTX completely abolished the spike and eliminated an inward current under voltage clamp, indicating that the action potential is due primarily to a sodium current. Calcium-free saline had no effect on spike waveform or voltage-clamp currents, indicating that neither calcium nor calcium-dependent currents contribute to the action potential. Application of potassium channel blocking agents, such as tetraethylammonium and cesium ions, caused changes in the spike which, together with voltage-clamp results, indicate the presence of two potassium currents: an inward rectifier and a classical delayed rectifier. In addition, these cells have a large, presumably voltage-insensitive, chloride current. Differences in one or more of these currents could be responsible for the range of action potential durations found in these cells and for the steroid-mediated changes in spike duration.

Action Potentials↗
PubMed1992

Therapeutic potential of modulating potassium currents in the diseased myocardium.

Myocardial disease states are characterized by multiple electrophysiologic abnormalities, including alterations in potassium channel activities. During acute myocardial ischemia, activation of ATP-regulated K+ current (IK(ATP)) results in shortening of action potential duration and elevation of extracellular K+ concentration. In hypertrophied myocardium, increases in inward rectifier K+ current (IK1) and decreases in delayed rectifier K+ current (IK) are observed. Alterations in K+ channel activity in myocardial disease states suggest the potential to therapeutically modify cardiac rhythm and function with K+ channel modulators. Class III anti-arrhythmic agents, which prolong myocardial refractoriness predominantly via a blockade of IK, have demonstrated efficacy in suppressing reentrant atrial and ventricular arrhythmias in animal models as well as promising efficacy in initial clinical studies. Potassium channel openers (PCOs), which activate cardiac IK(ATP), have demonstrated both antiarrhythmic and proarrhythmic activities in various experimental settings, and also are being investigated as potential cardioprotective agents. Sulfonylureas, which block cardiac IK(ATP), also have been investigated as potential antiarrhythmic agents with equivocal results, and have displayed a propensity to exacerbate ischemic myocardial dysfunction in experimental studies. A more comprehensive understanding of K+ channel activity in various myocardial disease states, including concomitant disorders such as myocardial ischemia and hypertrophy, will facilitate the development of more useful potassium channel modulators, as well as a clearer recognition of the undesirable effects of such agents.

Animals↗
PubMed1994

Demonstration of voltage-dependent and TTX-sensitive Na(+)-channels in human melanocytes.

The electrophysiological properties of cultured human melanocytes were investigated using the whole-cell configuration of the patch-clamp technique. Depolarizations to membrane potentials more positive than -30 mV resulted in the rapid development ( < 1 ms to peak) of an inward current. The maximum peak current was observed at +10 mV and reached an average amplitude of about 270 pA. During the depolarizations, the current inactivated with a time constant of about 2 ms. The current was abolished by the addition of 0.3 microM tetrodotoxin, a blocker of voltage-gated Na(+)-channels, and disappeared when Na+ was omitted from the extracellular medium. In addition, the melanocytes contain at least two types of outward K(+)-current. The first type, observed in every cell, was highly sensitive (Ki 1 mM) to the K(+)-channel blocker TEA, required depolarizations beyond zero to be activated and did not inactivate. The second type was less regularly observed (10% of the cells). This current activated at more negative voltages (-20 mV), was resistant to TEA (20 mM) but was blocked by 2 mM 4-aminopyridine and inactivated rapidly during depolarizations. We conclude that human melanocytes are equipped with voltage-dependent Na(+)-channels, a delayed rectifying K(+)-current and a K(+)-current similar to the A-current in neurones.

4-Aminopyridine↗
PubMed1982

Block of outward current in cardiac Purkinje fibers by injection of quaternary ammonium ions.

We have studied the effects of iontophoretic injection of the quaternary ammonium compounds tetraethylammonium (TEA) and tetrabutylammonium (TBA) in cardiac purkinje fibers. We find that TBA(+) is a more effective blocker than TEA(+), but injection of either compound reduces the time-dependent outward plateau currents, transient outward current (I(to)), and the delayed rectifier (I(x)). Our findings provide evidence that these outward cardiac currents are carried by channels that in some respects are pharmacologically similar to squid axon potassium channels. We demonstrate that this procedure is a new tool that can be useful in the analysis of membrane currents in the heart.

Animals↗
PubMed1999

Inward rectifier potassium conductance regulates membrane potential of canine colonic smooth muscle.

1. The membrane potential of gastrointestinal smooth muscles determines the open probability of ion channels involved in rhythmic electrical activity. The role of Ba2+-sensitive K+ conductances in the maintenance of membrane potential was examined in canine proximal colon circular muscle. 2. Application of Ba2+ (1-100 microM) to strips of tunica muscularis produced depolarization of cells along the submucosal surface of the circular muscle layer. Significantly higher concentrations of Ba2+ were needed to depolarize preparations from which the submucosal and myenteric pacemaker regions were removed. 3. Elevation of extracellular [K+]o (from 5.9 to 12 mM) brought membrane potentials closer to EK (the Nernst potential for K+ ions), suggesting activation of a K+ conductance. This occurred at potentials much more negative than the activation range for delayed rectifier channels (Kv). 4. Forskolin (1 microM) caused hyperpolarization and a leftward shift in the dose-response relationship for Ba2+, suggesting that forskolin may activate a Ba2+-sensitive conductance. 5. Patch-clamp recordings from interstitial cells of Cajal (ICC) revealed the presence of a Ba2+-sensitive inward rectifier potassium conductance. Far less of this conductance was present in smooth muscle cells. 6. Kir2.1 was expressed in the circular muscle layer of the canine proximal colon, duodenum, jejunum and ileum. Kir2.1 mRNA was expressed in greater abundance along the submucosal surface of the circular muscle layer in the colon. 7. These results demonstrate that ICC express a Ba2+-sensitive conductance (possibly encoded by Kir2.1). This conductance contributes to the generation and maintenance of negative membrane potentials between slow waves.

Animals↗
PubMed1990

A delayed rectifier potassium current in Xenopus oocytes.

A delayed voltage-dependent K+ current endogenous to Xenopus oocytes has been investigated by the voltage-clamp technique. Both activation and inactivation of the K+ current are voltage-dependent processes. The K+ currents were activated when membrane potential was depolarized from a holding potential of -90 to -50 mV. The peak current was reached within 150 ms at membrane potential of +30 mV. Voltage-dependent inactivation of the current was observed by depolarizing the membrane potential from -50 to 0 mV at 10-mV increments. Voltage-dependent inactivation was a slow process with a time constant of 16.5 s at -10 mV. Removal of Ca2+ from the bath has no effect on current amplitudes, which indicates that the current is Ca2+)-insensitive. Tail current analysis showed that reversal potentials were shifted by changing external K+ concentration, as would be expected for a K(+)-selective channel. The current was sensitive to quinine, a K+ channel blocker, with a Ki of 35 microM. The blockade of quinine is voltage-independent in the range of -20 to +60 mV. Whereas oocytes from the same animal have a relatively homogeneous current distribution, average amplitude of the K+ current varied among oocytes from different animals from 30 to 400 nA at membrane potential of +30 mV. Our results indicate the presence of the endogenous K+ current in Xenopus oocytes with characteristics of the delayed rectifier found in some nerve and muscle cells.

Animals↗
PubMed1993

Voltage-dependent potassium currents in cultured human retinal pigment epithelial cells.

Membrane currents in primary cultures of human retinal pigment epithelial cells were studied using the whole-cell configuration of the patch-clamp technique. Two types of voltage-dependent whole-cell currents were observed. First, a time- and voltage-dependent outward current, which was activated by depolarizing the cell to potentials more positive than -30mV, was sensitive to Ba2+ (10mM), 4-aminopyridine (10mM) and TEA+ (30mM). Tail-current analysis indicated that the current was mainly carried by K(+)-ions. Second, hyperpolarization of the cell to potentials more negative than -70mV led to a time- and voltage-dependent inward current which was blocked by Ba2+ (10mM) and 4-aminopyridine (10mM), but not by TEA+ (30mM). In summary, human retinal pigment epithelial cells in primary culture express currents which indicate the presence of a delayed rectifier K(+)-channel and an inward rectifier K(+)-channel.

4-Aminopyridine↗
PubMed1993

Redistribution of K+ channels into dendrites is unlikely to account for developmental down regulation of A-currents in rat dentate gyrus granule cells.

The electrical reactions of many central neurons depend on two voltage-activated K+ currents: the fast transient A-current IA and the delayed rectifier current IK. In rat dentate gyrus granule cells, the A-current density decreases during ontogenesis, possibly due to a redistribution of K+ channels from somata into dendrites. We tested this possibility in mechanically isolated granule cells with preserved dendrites of different length. Potassium currents were recorded with the whole-cell patch-clamp technique using prepulse protocols with and without a delay interval to isolate IA. A correlation between the length of the dendrites and the amount of A-current expressed in a given cell could not be demonstrated. Our findings therefore confirm an ontogenetic down regulation of A-currents.

Animals↗
PubMed1986

Changes in the expression of potassium channels during mouse T cell development.

In this report we have combined the whole-cell electrophysiological recording technique with flow microfluorometry to isolate phenotypically defined thymocytes and T lymphocytes. Results obtained showed that J11d-/Lyt-2-/L3T4- cells express none or very few delayed rectifier K+ channels, whereas most other Lyt-2-/L3T4- cells, as well as typical cortical thymocytes (Lyt-2+/L3T4+), do express K+ channels. Mature (Lyt-2+/L3T4- or Lyt-2-/L3T4+) thymocytes, which are heterogeneous for J11d expression, were also found to be heterogeneous for K+ channel expression. Consistent with this finding was the observation that the cortisone-resistant subpopulation of thymocytes, which express low levels of J11d, were enriched for cells expressing low levels of K+ channels. Mature phenotype peripheral T lymphocytes expressed very low levels of K+ channels, but upon activation with Con A were found to express high levels of K+ channels. The results suggest that K+ channel expression in T cells is developmentally regulated. Increased expression of the channel is induced in response to mitogenic signals throughout the T cell lineage. Expression of the channel, therefore, serves as a useful marker in defining steps in the T cell differentiation pathway.

Animals↗
PubMed1993

4,5-Dihydro-1-phenyl-1H-2,4-benzodiazepines: novel antiarrhythmic agents.

A series of 4,5-dihydro-1-phenyl-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact with sodium and potassium channels and prolong the ventricular effective refractory period (ERP) in anesthetized guinea pigs. Concomitant displacement of radiolabeled bactrachotoxin from site II in Na+ channels and of radiolabeled dofetilide from delayed rectifier K+ channels was evident with all members of this chemical series at a concentration of 10 microM. Structure-activity relationship (SAR) studies using a paced guinea pig model to assess prolongation of the ERP indicated that methyl or ethyl at the 1-position had little effect on activity, while larger groups caused a diminution of activity. Compounds with substituents at either the 3- or 4-position that increased lipophilicity generally were more potent; however, too many lipophilic substituents simultaneously at positions 1, 3, and 4 resulted in less active compounds. Substituents on either aromatic ring had little influence on activity, and phenyl at the 5-position resulted in a significant reduction in antiarrhythmic activity. When two sets of enantiomerically pure compounds were tested in the guinea pig, chirality was shown to be important for activity of 8, where the (R)-enantiomer was the more active, but not in the case of 15, where the enantiomers were equiactive. Several compounds in this series increased the threshold for ventricular fibrillation and refractoriness in myocardially-infarcted anesthetized cata and delayed the onset of aconitine-induced arrhythmias in anesthetized guinea pigs following intravenous dosing. Moreover, these compounds possessed oral antiarrhythmic activity in conscious myocardially-infarcted dogs. Compound R-15 has been advanced for further biological and toxicological evaluations.

Animals↗
PubMed1999

Blockade of HERG channels expressed in Xenopus oocytes by external H+.

We have investigated the effect of external H+ concentration ([H+]o) on the human-ether-a-go-go-related gene (HERG) current (IHERG), the molecular equivalent of the cardiac delayed rectifier potassium current (IKr), expressed in Xenopus oocytes, using the two-microelectrode voltage-clamp technique. When [H+]o was increased, the amplitude of the IHERG elicited by depolarization decreased, and the rate of current decay on repolarization was accelerated. The activation curve shifted to a more positive potential at lower external pH (pHo) values (the potential required for half-maximum activation, V1/2, was: -41.8 mV, -38.0 mV, -33.7 mV, -26.7 mV in pHo 8.0, 7.0, 6.6, 6.2, respectively). The maximum conductance (gmax) was also affected by [H+]o: a reduction of 7.9%, 14.6%, and 22.8% was effected by decreasing pHo from 8.0 to 7.0, 6.6, and 6.2, respectively. We then tested whether this pH effect was affected by the external Ca2+ concentration, which is also known to block HERG channels. When the extracellular Ca2+ concentration was increased from 0.5 mM to 5 mM, the shift in V1/2 caused by increasing [H+]o was attenuated, suggesting that these two ions compete for the same binding site. On the other hand, the decrease in gmax caused by increasing [H+]o was not significantly affected by changing external Ca2+ levels. The results indicate that HERG channels are inhibited by [H+]o by two different mechanisms: voltage-dependent blockade (shift of V1/2) and the decrease in gmax. With respect to the voltage-dependent blockade, the interaction between H+ and Ca2+ is competitive, whereas for the decreasing gmax, their interaction is non-competitive.

Animals↗
PubMed1999

Stimulus processing by type II hair cells in the mouse utricle.

In type II and neonatal hair cells in the mouse utricle, the receptor potentials evoked by low-frequency sinusoidal deflections of the hair bundle are attenuated by adaptation of the mechanoelectrical transduction current and the voltage-dependent activation of a large potassium (K)-selective outwardly rectifying conductance, gDR. These processes may contribute to high-pass filtering of the responses of some utricular afferents to sinusoidal linear accelerations below 2 Hz. Depolarizing receptor potentials are more attenuated by gDR than are hyperpolarizing receptor potentials. It may therefore reduce nonlinear distortion introduced by mechanoelectrical transduction, which generates larger depolarizing currents than hyperpolarizing currents. The discharge properties of utricular afferents vary according to whether they innervate the striolar or extrastriolar zones of the sensory epithelium. Regional variation in hair-cell properties is likely to contribute. Preliminary results suggest that the outwardly rectifying K conductances of type II cells are slower and larger in the striola than in the extrastriola, consistent with regional variation in the relative numbers of delayed rectifier and A-current K channels.

Animals↗