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Results for “Delayed Rectifier Potassium Channels”

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PubMed2000

Effects of experimental heart failure on atrial cellular and ionic electrophysiology.

BACKGROUND: Congestive heart failure (CHF) is frequently associated with atrial fibrillation (AF), but little is known about the effects of CHF on atrial cellular electrophysiology. METHODS AND RESULTS: We studied action potential (AP) properties and ionic currents in atrial myocytes from dogs with CHF induced by ventricular pacing at 220 to 240 bpm for 5 weeks. Atrial myocytes from CHF dogs were hypertrophied (mean+/-SEM capacitance, 89+/-2 pF versus 71+/-2 pF in control, n=160 cells per group, P<0.001). CHF significantly reduced the density of L-type Ca(2+) current (I(Ca)) by approximately 30%, of transient outward K(+) current (I(to)) by approximately 50%, and of slow delayed rectifier current (I(Ks)) by approximately 30% without altering their voltage dependencies or kinetics. The inward rectifier, ultrarapid and rapid delayed rectifier, and T-type Ca(2+) currents were not altered by CHF. CHF increased transient inward Na(+)/Ca(2+) exchanger (NCX) current by approximately 45%. The AP duration of atrial myocytes was not altered by CHF at slow rates but was increased at faster rates, paralleling in vivo refractory changes. CHF created a substrate for AF, prolonging mean AF duration from 8+/-4 to 535+/-82 seconds (P<0.01). CONCLUSIONS: Experimental CHF selectively decreases atrial I(to), I(Ca), and I(Ks), increases NCX current, and leaves other currents unchanged. The cellular electrophysiological remodeling caused by CHF is quite distinct from that caused by atrial tachycardia, highlighting important differences in the cellular milieu characterizing different clinically relevant AF substrates.

Action Potentials↗

PubMed1998

Effects of the diuretic agent indapamide on Na+, transient outward, and delayed rectifier currents in canine atrial myocytes.

The diuretic agent indapamide has been reported to block the slow component of the delayed rectifier K+ current (IKs) without altering the rapid component (IKr) or the inward rectifier current and has been used as a pharmacological probe for IKs; however, the effects of indapamide on Na+ (INa), L-type Ca2+ (ICa), and transient outward K+ (Ito) currents have not been determined. We applied tight-seal, whole-cell, patch-clamp techniques to assess the effects of indapamide on INa, Ito, ICa, and IKs in canine atrial myocytes. Indapamide inhibited INa, Ito, and IKs in a concentration-dependent and reversible way, without altering ICa. Block increased with depolarization, with the 50% blocking concentration (EC50) decreasing from 129 +/- 26 micromol/L (at -60 mV) to 79 +/- 17 micromol/L (at -10 mV) for INa, from 174 +/- 19 micromol/L (at + 10 mV) to 98 +/- 7 micromol/L (at +60 mV) for Ito and from 148 +/- 28 micromol/L (at +10 mV) to 86 +/- 18 micromol/L (at +60 mV) for IKs. Significant inhibition was seen at concentrations as low as 10 micromol/L for all 3 currents. In addition, indapamide effectively inhibited the ultrarapid delayed rectifier current in a voltage-independent way, with an EC50 of 138 +/- 7 micromol/L at +10 mV. Standard microelectrode experiments showed the effects of indapamide on the action potential to be consistent with the ionic actions seen. We conclude that in addition to its well-recognized IKs-blocking action, indapamide also inhibits INa and Ito effectively and with similar potency. Thus, indapamide is not a reliable pharmacological probe with which to study the specific effects of IKs blockade, and INa and Ito block may contribute to the potential profile of cardiac actions of the compound.

Action Potentials↗

PubMed1999

Effects of itopride hydrochloride on the delayed rectifier K+ and L-type CA2+ currents in guinea-pig ventricular myocytes.

The effects of itopride hydrochloride, a new drug used to regulate motility in the gastrointestinal tract, on the delayed rectifier K+ current (I(K)) and the L-type Ca2+ current (I(Ca)) were evaluated in guinea-pig ventricular myocytes at concentrations of 1, 10 and 100 microM to determine whether the drug has a proarrhythmic effect through blockade of I(K). Itopride did not affect I(K) at concentrations of 100 microM or less, and no significant effects of 1, 10 or 100 microM itopride were observed on the inward rectifier K+ current (I(K1)) responsible for the resting potential and final repolarization phase of the action potential. We next investigated the effects of itopride on L-type Ca2+ current (I(Ca)). Significant inhibition of I(Ca) was observed at itopride concentrations greater than 10 microM. These results suggested that itopride hydrochloride has an inhibitory effect on I(Ca) at concentrations much higher than those in clinical use.

Action Potentials↗

PubMed1998

Activation kinetics of the delayed rectifier potassium current of bullfrog sympathetic neurons.

We examined the activation kinetics of the delayed rectifier K+ current of bullfrog sympathetic neurons, primarily using whole cell recording. On depolarization, currents activated with a sigmoid delay but did not show a Cole-Moore shift. The time course of activation differed systematically from an exponential raised to a power. At most voltages, a power of 2 gave the best overall fit but a power of 3 better described the initial delay. After the delay, the time course could be fitted by a single exponential. Time constants were 15-20 ms at 0 mV and decreased to a limiting tau = 7 ms at +50 to +100 mV. Tail currents were well fitted by single exponential functions and accelerated with hyperpolarization, from tau = 15-20 ms at 0 mV to tau = 2 ms at -110 mV (e-fold for 40 mV). Eleven kinetic models were evaluated for their ability to describe the activation kinetics of the delayed rectifier. Hodgkin-Huxley-like models did not fit the data well. A linear model where voltage sensor movement is followed by a distinct channel opening step, allosteric models based on the Monod-Wyman--Changeux model, and an unconstrained C-C-C-O model could describe whole cell data from -100 to +40 mV. After including whole cell data at +60 and +80 mV, and a maximal p(open) of 0.8 from noise analysis of cell-attached patches, an allosteric model fit the data best, as the other models had difficulty describing qualitative features of the data. However, some more complex schemes (with additional free parameters) cannot be excluded. We propose the allosteric model as an empirical description of macroscopic ionic currents, and as a model worth considering in future studies on the molecular mechanism of potassium channel gating.

Animals↗

PubMed1999

Parathyroid hypertensive factor inhibits voltage-gated K+ channels in vascular smooth muscle cells.

Parathyroid hypertensive factor (PHF) has been implicated in regulation of vascular smooth muscle tone and pathogenesis of several forms of hypertension. Earlier studies have suggested that PHF enhances the actions of other vasoconstrictors, while it has no in vitro vasoconstrictor property of its own. PHF was previously found to enhance the L-type Ca channel currents and intracellular Ca responses to depolarization in vascular smooth muscle cells (VSMCs). The present study examined whether PHF might act on K channels in the plasma membrane of VSMCs. Primary cultured VSMCs from rat tail artery were used. The whole-cell version of the patch-clamp technique was used under conditions in which there was no contribution of Ca-activated K channels to the outward current. Both purified and semipurified PHF inhibited the delayed rectifier type potassium current in a dose-dependent manner. The effect was time dependent and was first significantly different from the control current after 30 min. The inhibition of the delayed rectifier K channel was associated with a time-dependent decrease in the resting membrane potential. Therefore, PHF may alter VSMC cellular Ca responses by reducing the membrane potential to a level closer to the activation potential of Ca channels.

Animals↗

PubMed1998

Cardiac actions of taurine as a modulator of the ion channels.

During ischemia, hypoxia and cardiac failure, the heart undergoes several adverse changes, including a reduction in taurine (2-aminoethanesulfonic acid). Oral administration of taurine under these disease conditions would be expected to act like a mild cardiac glycoside. Taurine would exert improvement in the accumulation of [Na]i and the loss of alpha-amino acids. Nonetheless, when intracellular taurine content is raised, there would be the benefit of increased Ca2+ release from the sarcoplasmic reticulum and increased Ca2+ sensitivity of the contractile proteins, as well as possible changes in the action potential associated with the actions of taurine on ion channels. In fact, intracellular application of taurine produces the opposite actions to extracellularly administration of the amino acid. From our previous experiments, the electrophysiological actions of taurine on cardiac muscle cells include the following. (a) Prolongation of action potential duration (APD) at high [Ca]i and shortening of APD at low [Ca]i. In multicellular preparations, however, taurine did not always prevent [Ca]o-induced effects. (b) Stimulation of spontaneous activity at low intracellular and extracellular Ca2+ concentrations ([Ca]i and [Ca]o), and vice versa. (c) Inhibition of the L-type Ca2+ current (ICa(L)) at high [Ca]i, and vice versa. (d) Enhancement of the T-type Ca2+ current (ICa(T)). (e) Inhibition of fast Na+ current (INa). (f) Enhancement of TTX-insensitive slow Na+ current. (g) Inhibition of delayed rectifier K+ current (IKrec) at high [Ca]i, and vice versa. (h) Enhancement of the transient outward current (Ito). (i) Inhibition of the ATP-sensitive K+ current (IK(ATP)). Since taurine acts on so many ion channels and transporters, it is clearly non-specific. Although it is very difficult to understand the diversity of taurine's actions, it is possible that taurine can exert its potent cardioprotective actions under the conditions of low [Ca]i, as well as Ca2+ overload. Thus, although taurine-induced modulation of ion channels located on the cardiac cell membrane is complex, the multiple effects may combine to yield useful therapeutic results.

Adenosine Triphosphate↗

PubMed2006

Acute estradiol application increases inward and decreases outward whole-cell currents of neurons in rat hypothalamic ventromedial nucleus.

Acute estradiol (E2) can potentiate the excitatory responses of hypothalamic ventromedial nucleus (VMN) neurons to neurotransmitters. To investigate the mechanism(s) underlying the potentiation, the whole-cell patch voltage clamp technique was used to study VMN neurons in hypothalamic slices prepared from female juvenile (3-5 weeks) rats. A voltage step and/or ramp was applied every 5 min to evoke whole-cell currents before, during and after a treatment with E2 (10 nM), corticosterone (10 nM) or vehicle for up to 20 min. Acute E2 increased inward currents in 38% of neurons tested. Their average peak inward current amplitudes started to increase within 5 min and reached the maximum of 163% of pretreatment level (Pre) at 20 min of treatment before recovering toward Pre. These increases are significantly greater than the Pre and corresponding vehicle controls and non-responsive neurons. Outward currents were decreased significantly by E2 in 27% of E2-treated cells, down to 60% of Pre levels. E2 also appeared to affect the kinetics of the inward and outward currents of estrogen-responsive neurons. Whenever observed, the effects of acute E2 were reversible after a 5- to 10-min washing. Probability analysis indicates that E2 affected the inward and the outward currents independently. The E2 effects are specific in that they were not produced by similar treatment with vehicle or corticosterone. Pharmacological characterizations using ion replacement and channel blockers showed that the inward currents were mediated practically all by Na(+) and the outward currents mainly by K(+). Thus, acute E2 can enhance inward Na(+) and attenuate outward K(+) currents. Since both effects will lead to an increase in neuronal excitability, they may explain our previous observation that E2 potentiates the excitation of VMN neurons.

Animals↗

PubMed2004

Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig.

Beat-to-beat alternations of the cardiac monophasic action potential, known as electrical alternans, were studied at drug concentrations that have known arrhythmogenic outcomes. Electrical alternans were elicited from the heart of anesthetized guinea pigs, both in the absence and presence of drugs that inhibit the delayed rectifier K(+) channel encoded by the human ether a-go-go related-gene (HERG), and are associated with the fatal arrhythmia, Torsade de Pointes. Two other HERG inhibiting drugs not associated with Torsade de Pointes were also studied. At concentrations known to be proarrhythmic, E-4031 and bepridil increased mean alternans 10 and 40 ms at pacing frequencies </=160 ms. Terfenadine and cisapride both increased mean alternans up to 20 and 21 ms, respectively, at pacing frequencies of </=150 ms. On the other hand, verapamil and risperidone showed no increase in mean alternans while risperidone significantly reduced alternans at concentrations up to 74 times its therapeutic level. The magnitude of effect on rate-dependent alternans may allow the differentiation of proarrhythmia and non-arrhythmic HERG blockers at clinically relevant concentrations.

Animals↗

PubMed2005

Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation.

I(Ks), the slowly activating component of the delayed rectifier current, plays a major role in repolarization of the cardiac action potential (AP). Genetic mutations in the alpha- (KCNQ1) and beta- (KCNE1) subunits of I(Ks) underlie Long QT Syndrome type 1 and 5 (LQT-1 and LQT-5), respectively, and predispose carriers to the development of polymorphic ventricular arrhythmias and sudden cardiac death. beta-adrenergic stimulation increases I(Ks) and results in rate dependent AP shortening, a control system that can be disrupted by some mutations linked to LQT-1 and LQT-5. The mechanisms by which I(Ks) regulates action potential duration (APD) during beta-adrenergic stimulation at different heart rates are not known, nor are the consequences of mutation induced disruption of this regulation. Here we develop a complementary experimental and theoretical approach to address these questions. We reconstituted I(Ks) in CHO cells (ie, KCNQ1 coexpressed with KCNE1 and the adaptator protein Yotiao) and quantitatively examined the effects of beta-adrenergic stimulation on channel kinetics. We then developed theoretical models of I(Ks) in the absence and presence of beta-adrenergic stimulation. We simulated the effects of sympathetic stimulation on channel activation (speeding) and deactivation (slowing) kinetics on the whole cell action potential under different pacing conditions. The model suggests these kinetic effects are critically important in rate-dependent control of action potential duration. We also investigate the effects of two LQT-5 mutations that alter kinetics and impair sympathetic stimulation of I(Ks) and show the likely mechanism by which they lead to tachyarrhythmias and indicate a distinct role of I(KS) kinetics in this electrical dysfunction. The full text of this article is available online at http://circres.ahajournals.org.

A Kinase Anchor Proteins↗

PubMed1995

Quaternary ammonium ion blockade of IK in nerve axons revisited. Open channel block vs. state independent block.

The mechanism of blockade of the delayed rectifier potassium ion channel in squid giant axons by intracellular quaternary ammonium ions (QA) appears to be remarkably sensitive to the structure of the blocker. TEA, propyltriethyl-ammonium (C3), and propyltetraethylammonium (TAA-C3) all fail to alter the deactivation, or "tail" current time course following membrane depolarization, even with relatively large concentrations of the blockers, whereas butyltriethylammonium (C4), butyltetraethylammonium (TAA-C4), and pentytriethyammonium (C5) clearly do have such an effect. The relative electrical distance of blockade for all of these ions is approximately 0.25-0.3 from the inner surface of the membrane. The observations concerning TEA, C3, and TAA-C3 suggest that these ions can block the channel in either its open or its closed state. The results with C4, TAA-C4, and C5 are consistent with the open channel block model. Moreover, the sensitivity of block mechanism to the structure of the blocker suggests that the gate is located close to the QA ion binding site and that TEA, C3, and TAA-C3 do not interfere with channel gating, whereas C4, TAA-C4, C5, and ions having a longer hydrophobic "tail" than C5 do have such an effect. The parameters of block obtained for all QA ions investigated were unaffected by changes in the extracellular potassium ion concentration.

Animals↗

PubMed1993

Block of delayed rectifier (DRK1) K+ channels by internal 2,3-butanedione monoxime in Xenopus oocytes.

Inhibition of delayed rectifier (DRK1) potassium channels by 2,3-butanedione monoxime (BDM) was investigated in inside-out membrane patches from Xenopus oocytes previously injected with in vitro transcribed DRK1 cRNA. Internally applied BDM (20 mM) rapidly and reversibly reduced peak macroscopic DRK1 current. 20 mM internal BDM increased the time constant of activation at all voltages (from 8.0 +/- 0.9 ms to 19.8 +/- 2.0 ms at zero mV, n = 6). Fluctuation analyses, and direct measurement of single channel currents, indicated that BDM reduced open probability (P0), and single channel current, at all voltages. The peak P0-voltage (V) relationship (estimated with a Boltzman equation) was shifted (from V0 = -29.3 +/- 4.6 to -9.4 +/- 2.7 mV) and shallowed (from Z = 2.8 +/- 0.2 to 1.8 +/- 0.15, n = 4) by BDM. In a simple sequential kinetic model of DRK1, the peak P0-V relationship, both in control and in BDM, was well fitted with the same V0 and Z (1.51 +/- 0.1 and -37.1 +/- 4 mV, respectively; n = 4) but with different voltage-independent rate constants. Thus, the effects of BDM on the kinetics of activation, the voltage-dependence of activation, and the rate of inactivation could be accounted for by assuming changes only in voltage-independent parameters.

Action Potentials↗

PubMed2005

Inhibitory action of L-type Ca2+ current by paeoniflorin, a major constituent of peony root, in NG108-15 neuronal cells.

The effects of paeoniflorin, a glycoside isolated from the root of Paeonia lactiflora, on ion currents in a mouse neuroblastoma and rat glioma hybrid cell line, NG108-15 were investigated. Paeoniflorin (1-300 microM) reversibly produced an inhibition of L-type voltage-dependent Ca2+ current (I(Ca,L)) in a concentration-dependent manner. Paeoniflorin caused no change in the overall shape of the current-voltage relationship of I(Ca,L). The IC50 value of paeoniflorin-induced inhibition of I(Ca,L) was 14 microM. However, neither adenosine deaminase (1 U/ml) nor 8-cyclopentyl-1, 3-dipropylxanthine (10 microM) could reverse the inhibition by paeoniflorin of I(Ca,L). Paeoniflorin (30 microM) shifted the steady-state inactivation curve of I(Ca,L) to more negative membrane potentials by approximately -10 mV. It also prolonged the recovery of I(Ca,L). The inhibitory effect of paeoniflorin on I(Ca,L) exhibited tonic and use-dependent characteristics. Paeoniflorin could effectively suppress I(Ca,L) evoked by action potential waveforms. Paeoniflorin at a concentration of 30 microM produce a slight inhibition of voltage-dependent Na+ current and delayed rectifier K+ current. Under current-clamp configuration, unlike adenosine, this compound decreased the firing of action potentials. Taken together, this study indicates that paeoniflorin can block L-type Ca2+ channels in NG108-15 cells in a mechanism unlinked to the binding to adenosine receptors. The effects of paeoniflorin on ion currents may partly, if not entirely, contribute to the underlying mechanisms through which it affects neuronal or neuroendocrine function.

Action Potentials↗

PubMed1999

Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes.

Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]am ino]-2-propanol), a beta-adrenoceptor-blocking agent with vasodilator properties, has been reported to produce dose-related improvements in left ventricular function and reduction in mortality in patients with chronic heart failure. However, its electrophysiological effects have not been elucidated. We studied ion channel and action potential modulation by carvedilol in rabbit ventricular preparations using whole-cell voltage-clamp and standard microelectrode techniques. In ventricular myocytes, carvedilol blocked the rapidly activating component of the delayed rectifier K+ current (I(Kr)) in a concentration-dependent manner (IC50 = 0.35 microM). This block was voltage- and time-independent; a prolongation of the depolarizing pulses from a holding potential of -50 mV to +10 mV within the range of 100-3000 ms did not affect the extent of I(Kr) block. Carvedilol also inhibited the L-type Ca2+ current (I(Ca)), the transient outward K+ current (I(to)) and the slowly activating component of the delayed rectifier K+ current (I(Ks)) with IC50 of 3.59, 3.34, and 12.54 microM, respectively. Carvedilol (0.3-30 microM) had no significant effects on the inward rectifier K+ current. In papillary muscles from rabbits pretreated with reserpine, action potential duration was prolonged by 7-12% with 1 microM and by 12-24% with 3 microM carvedilol at stimulation frequencies of 0.1-3.0 Hz. No further action potential duration prolongation was observed at concentrations higher than 3 microM. These results suggest that concomitant block of K+ and Ca2+ currents by carvedilol resulted in a moderate prolongation of action potential duration with minimal reverse frequency-dependence. Such electrophysiological effects of carvedilol would be beneficial in the treatment of ventricular tachyarrhythmias.

Action Potentials↗

PubMed2004

Nitric oxide-dependent modulation of the delayed rectifier K+ current and the L-type Ca2+ current by ginsenoside Re, an ingredient of Panax ginseng, in guinea-pig cardiomyocytes.

1 Ginsenoside Re, a major ingredient of Panax ginseng, protects the heart against ischemia-reperfusion injury by shortening action potential duration (APD) and thereby prohibiting influx of excessive Ca2+. Ginsenoside Re enhances the slowly activating component of the delayed rectifier K+ current (IKs) and suppresses the L-type Ca2+ current (I(Ca,L)), which may account for APD shortening. 2 We used perforated configuration of patch-clamp technique to define the mechanism of enhancement of IKs and suppression of I(Ca,L) by ginsenoside Re in guinea-pig ventricular myocytes. 3 S-Methylisothiourea (SMT, 1 microm), an inhibitor of nitric oxide (NO) synthase (NOS), and N-acetyl-L-cystein (LNAC, 1 mm), an NO scavenger, inhibited IKs enhancement. Application of an NO donor, sodium nitroprusside (SNP, 1 mm), enhanced IKs with a magnitude similar to that by a maximum dose (20 microm) of ginseonside Re, and subsequent application of ginsenoside Re failed to enhance IKs. Conversely, after IKs had been enhanced by ginsenoside Re (20 microm), subsequently applied SNP failed to further enhance IKs. 4 An inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microm), barely suppressed IKs enhancement, while a thiol-alkylating reagent, N-ethylmaleimide (NEM, 0.5 mm), clearly suppressed it. A reducing reagent, di-thiothreitol (DTT, 5 mm), reversed both ginsenoside Re- and SNP-induced IKs enhancement. 5 I(Ca,L) suppression by ginsenoside Re (3 microm) was abolished by SMT (1 microm) or LNAC (1 mm). NEM (0.5 mm) did not suppress I(Ca,L) inhibition and DTT (5 mm) did not reverse I(Ca,L) inhibition, whereas in the presence of ODQ (10 microm), ginsenoside Re (3 microm) failed to suppress I(Ca,L). 6 These results indicate that ginsenoside Re-induced IKs enhancement and I(Ca,L) suppression involve NO actions. Direct S-nitrosylation of channel protein appears to be the main mechanism for IKs enhancement, while a cGMP-dependent pathway is responsible for I(Ca,L) inhibition.

Action Potentials↗

PubMed2004

Molecular profile of vascular ion channels after experimental subarachnoid hemorrhage.

Cerebral vasospasm is a transient, delayed constriction of cerebral arteries that occurs after subarachnoid hemorrhage (SAH). Smooth muscle cells show impaired relaxation after SAH, which may be caused by a defect in the ionic mechanisms regulating smooth muscle membrane potential and Ca(2+) permeability. We tested this hypothesis by examining changes in expression of mRNA and protein for ion channels in the basilar arteries of dogs after SAH using quantitative real-time polymerase chain reaction (PCR) and western blotting. SAH was associated with a significant reduction in basilar artery diameter to 41 +/- 8% of pre-SAH diameter (P < 0.001) after 7 days. There was significant downregulation of the voltage-gated K(+) channel K(v) 2.2 (65% reduction in mRNA, P < 0.001; 49% reduction in protein, P < 0.05) and the beta1 subunit of the large-conductance, Ca(2+) - activated K(+) (BK) channel (53% reduction in mRNA, P < 0.02). There was no change in BK beta1 subunit protein. Changes in mRNA levels of K(v) 2.2 and the BK-beta1 subunit correlated with the degree of vasospasm (r(2) = 0.490 and 0.529 respectively, P < 0.05). The inwardly rectifying K(+) (K(ir)) channel K(ir) 2.1 was upregulated (234% increase in mRNA, P < 0.001; 350% increase in protein, P < 0.001). There was no significant change in mRNA expression of L- type Ca(2+) channels and the BK-alpha subunit. These data suggest that K(+) channel dysfunction may contribute to the pathogenesis of cerebral vasospasm.

Animals↗

PubMed2006

Sarcoplasmic reticulum Ca2+ release and depletion fail to affect sarcolemmal ion channel activity in mouse skeletal muscle.

In skeletal muscle, sarcoplasmic reticulum (SR) Ca2+ depletion is suspected to trigger a calcium entry across the plasma membrane and recent studies also suggest that the opening of channels spontaneously active at rest and possibly involved in Duchenne dystrophy may be regulated by SR Ca2+ depletion. Here we simultaneously used the cell-attached and whole-cell voltage-clamp techniques as well as intracellular Ca2+ measurements on single isolated mouse skeletal muscle fibres to unravel any possible change in membrane conductance that would depend upon SR Ca2+ release and/or SR Ca2+ depletion. Delayed rectifier K+ single channel activity was routinely detected during whole-cell depolarizing pulses. In addition the activity of channels carrying unitary inward currents of approximately 1.5 pA at -80 mV was detected in 17 out of 127 and in 21 out of 59 patches in control and mdx dystrophic fibres, respectively. In both populations of fibres, large whole-cell depolarizing pulses did not reproducibly increase this channel activity. This was also true when, repeated application of the whole-cell pulses led to exhaustion of the Ca2+ transient. SR Ca2+ depletion produced by the SR Ca2+ pump inhibitor cyclopiazonic acid (CPA) also failed to induce any increase in the resting whole-cell conductance and in the inward single channel activity. Overall results indicate that voltage-activated SR Ca2+ release and/or SR Ca2+ depletion are not sufficient to activate the opening of channels carrying inward currents at negative voltages and challenge the physiological relevance of a store-operated membrane conductance in adult skeletal muscle.

Animals↗

PubMed2003

Roles of L-type Ca2+ and delayed-rectifier K+ currents in sinoatrial node pacemaking: insights from stability and bifurcation analyses of a mathematical model.

To elucidate the dynamical mechanisms of the sinoatrial (SA) node pacemaker activity, we investigated the roles of L-type Ca2+ (ICa,L) and delayed-rectifier K+ (IKr) currents in pacemaking by stability and bifurcation analyses of our rabbit SA node model (Kurata Y, Hisatome I, Imanishi S, and Shibamoto T. Am J Physiol Heart Circ Physiol 283: H2074-H2101, 2002). Equilibrium points (EPs), periodic orbits, stability of EPs, and Hopf bifurcation points were calculated as functions of conductance or gating time constants of the currents for constructing bifurcation diagrams. Structural stability (robustness) of the system was also evaluated by computing stability and dynamics during applications of constant bias currents (Ibias). Blocking ICa,L or IKr caused stabilization of an EP and cessation of pacemaking via a Hopf bifurcation. The unstable zero-current potential region determined with Ibias applications, where spontaneous oscillations appear, shrunk and finally disappeared as ICa,L diminished, but shrunk little when IKr was eliminated. The reduced system, including no time-dependent current except ICa,L, exhibited pacemaker activity. These results suggest that ICa,L is responsible for EP instability and pacemaker generation, whereas IKr is not necessarily required for constructing a pacemaker cell system. We further explored the effects of various K+ currents with different kinetics on stability and dynamics of the model cell. The original IKr of delayed activation and inward rectification appeared to be most favorable for generating large-amplitude oscillations with stable frequency, suggesting that IKr acts as an oscillation amplifier and frequency stabilizer. IKr may also play an important role in preventing bifurcation to quiescence of the system.

Animals↗

PubMed2001

Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms.

Zinc and copper are highly concentrated in several mammalian brain regions, including the olfactory bulb and hippocampus. Whole cell electrophysiological recordings were made from rat olfactory bulb neurons in primary culture to compare the effects of zinc and copper on synaptic transmission and voltage-gated ion channels. Application of either zinc or copper eliminated GABA-mediated spontaneous inhibitory postsynaptic potentials. However, in contrast to the similarity of their effects on inhibitory transmission, spontaneous glutamate-mediated excitatory synaptic activity was completely blocked by copper but only inhibited by zinc. Among voltage-gated ion channels, zinc or copper inhibited TTX-sensitive sodium channels and delayed rectifier-type potassium channels but did not prevent the firing of evoked single action potentials or dramatically alter their kinetics. Zinc and copper had distinct effects on transient A-type potassium currents. Whereas copper only inhibited the A-type current, zinc modulation of A-type currents resulted in either potentiation or inhibition of the current depending on the membrane potential. The effects of zinc and copper on potassium channels likely underlie their effects on repetitive firing in response to long-duration step depolarizations. Copper reduced repetitive firing independent of the initial membrane voltage. In contrast, whereas zinc reduced repetitive firing at membrane potentials associated with zinc-mediated enhancement of the A-type current (-50 mV), in a significant proportion of neurons, zinc increased repetitive firing at membrane potentials associated with zinc-mediated inhibition of the A-type current (-90 mV). Application of zinc or copper also inhibited voltage-gated Ca(2+) channels, suggesting a possible role for presynaptic modulation of neurotransmitter release. Despite similarities between the effects of zinc and copper on some ligand- and voltage-gated ion channels, these data suggest that their net effects likely contribute to differential modulation of neuronal excitability.

Action Potentials↗