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PubMed2001

Kv2 channels form delayed-rectifier potassium channels in situ.

A non inactivating potassium current known as the delayed rectifier plays a major role in membrane repolarization during an action potential. Whereas several candidate genes exist that code for potassium current, the identities of the molecular isotypes that are responsible in situ for membrane repolarization remain unidentified. We report that Kv2 channels play a major role in action potential repolarization. Kv2 channel elimination resulted in a reduction of the density of noninactivating potassium current and a prolonged impulse duration. In contrast, suppression of noninactivating current carried by Kv1 channels was much less effective in increasing action potential durations. Thus, whereas different potassium channels encode sustained potassium current, their contributions to action potential repolarization vary and require direct examination in situ. Our results indicate that Kv2 subunits function as classic delayed-rectifier channels in vertebrate neurons.

Action Potentials↗

PubMed1990

Sialic acid and the surface charge of delayed rectifier potassium channels.

We used the whole-cell configuration of the patch-clamp technique and cultured ventricular myocytes from 7-day embryonic chicks to test the hypothesis that sialic acid residues (NANA) constitute the negative surface charge associated with delayed rectifier potassium channels. Delayed rectifier current (iK) was elicited at potentials between -40 and +60 mV. The existence of negative fixed charges close to the "gating sensor" was confirmed by a 6.8-mV negative shift of the half-activation potential (V1/2) following a 10-fold reduction of divalent cations and a 22.6-mV position shift following the addition of 10 mM NiCl2. An 8.4-mV increase in the Boltzmann equation slope factor (k) in the former experiment and a 5.5-mV decline in the latter suggested that the surface charge is not uniformly distributed. We used a high performance liquid chromatography procedure to detect freed sarcolemmal NANA and found that 71-88% was released by neuraminidase (0.2-2.0 U/ml) during 1-h treatments. Such treatments had no significant effect upon the amplitudes of iK or V1/2. On the other hand, k was increased significantly by the enzyme (2.0 U/ml), but only when Ca2+ was present. Finally, 1-h pre-treatments with neuraminidase (2.0 U/ml) had no effect on the positive shift of V1/2 induced by Ni2+. We conclude that although sarcolemmal NANA may bind Ca2+, it does not constitute the surface charge of delayed rectifier potassium channels.

Animals↗

PubMed2002

The 25-kDa synaptosome-associated protein (SNAP-25) binds and inhibits delayed rectifier potassium channels in secretory cells.

Delayed-rectifier K(+) channels (K(DR)) are important regulators of membrane excitability in neurons and neuroendocrine cells. Opening of these voltage-dependent K(+) channels results in membrane repolarization, leading to the closure of the Ca(2+) channels and cessation of insulin secretion in neuroendocrine islet beta cells. Using patch clamp techniques, we have demonstrated that the activity of the K(DR) channel subtype, K(V)1.1, identified by its specific blocker dendrodotoxin-K, is inhibited by SNAP-25 in insulinoma HIT-T15 beta cells. A co-precipitation study of rat brain confirmed that SNAP-25 interacts with the K(V)1.1 protein. Cleavage of SNAP-25 by expression of botulinum neurotoxin A in HIT-T15 cells relieved this SNAP-25-mediated inhibition of K(DR). This inhibitory effect of SNAP-25 is mediated by the N terminus of K(V)1.1, likely by direct interactions with K(Valpha)1.1 and/or K(V)beta subunits, as revealed by co-immunoprecipitation performed in the Xenopus oocyte expression system and in vitro binding. Taken together we have concluded that SNAP-25 mediates secretion not only through its participation in the exocytotic SNARE complex but also by regulating membrane potential and calcium entry through its interaction with K(DR) channels.

Animals↗

PubMed1997

Effects of Pb2+ on delayed-rectifier potassium channels in acutely isolated hippocampal neurons.

Effects of Pb2+ on delayed-rectifier potassium channels in acutely isolated hippocampal neurons. J. Neurophysiol. 78: 2649-2654, 1997. The effects of Pb2+ on delayed-rectifier potassium currents were studied in acutely isolated hippocampal neurons (CA1 neurons, CA3 neurons, granule cells) from the guinea pig using the patch-clamp technique in the whole cell configuration. Pb2+ in micromolar concentrations decreased the potassium currents in a voltage-dependent manner, which appeared as a shift of the current-voltage relation to positive potentials. The effect was reversible after washing. The concentration-responsiveness measured in CA1 neurons revealed an IC50 value of 30 mu mol/l at a potential of -30 mV. The half-maximal shift of the current-voltage relation was reached at 33 mu mol/l and the maximal obtainable shift was 13.4 mV. For the different types of hippocampal neurons, the shift of the current-voltage relation was distinct and was 7.9 mV in CA1 neurons, 13.7 mV in CA3 neurons, and 14.2 mV in granule cells with 50 micro mol/l Pb2+. The effects described here of Pb2+ on the potassium currents in hippocampal neurons and the differences between the types of hippocampal neurons correspond with the known properties and distributions of cloned potassium channels found in the hippocampus. As a whole, our results demonstrate that Pb2+ in micromolar concentration is a voltage-dependent, reversible blocker of delayed-rectifier potassium currents of hippocampal neurons. This effect has to be taken into consideration as a possible contributing mechanism for the neurological symptoms of enhanced brain activity seen during Pb2+ intoxication.

4-Aminopyridine↗

PubMed1999

Changes in the mRNA levels of delayed rectifier potassium channels in human atrial fibrillation.

INTRODUCTION: We measured mRNA levels of delayed rectifier potassium channels in human atrial tissue to investigate the mechanism of the shortening of the atrial effective refractory period and the loss of rate-adaptive shortening of the atrial effective refractory period in human atrial fibrillation. METHODS AND RESULTS: A total of 34 patients undergoing open heart surgery were included. Atrial tissue was obtained from the right atrial free wall, right atrial appendage, left atrial free wall and left atrial appendage, respectively. The mRNA amounts of KVLQT1 (IKs), minK (beta-subunit of IKs), HERG (IKr), and KV1.5 (IKur) were measured by reverse transcription-polymerase chain reaction and normalized to the mRNA amount of GAPDH. We found that the mRNA levels of KV1.5, HERG and KVLQT1 were all significantly decreased in patients with persistent atrial fibrillation for more than 3 months. In contrast, the mRNA level of minK was significantly increased in patients with persistent atrial fibrillation for more than 3 months. We further showed that these changes were independent of the underlying cardiac disease, atrial filling pressure, gender and age. We also found that there was no spatial dispersion of mRNA levels among the four atrial sampling sites. CONCLUSIONS: Because the decrease in potassium currents results in a prolonged action potential, the shortening of the atrial effective refractory period in atrial fibrillation should be attributed to other factors. However, the decrease in IKs might contribute, at least in part, to the loss of rate-adaptive shortening of the atrial refractory period.

Adolescent↗

PubMed2003

[Effect of G protein in the dual regulation of opioid receptor agonist on the delayed rectified potassium channels].

OBJECTIVE: To observe the role of G protein in the dual regulation of opioid receptor agonist on the delayed rectified potassium channels. METHODS: Using whole-cell patch-clamp techniques applied to NG108-15 cells, investigate the effect of opioid receptor agonist on the delayed rectified potassium channels by administration of Guanosine-5'-0'-2-thiociphosphate (GDP beta S), Pertusis Toxin (PTX), Tetroacetic acid nueleoside diphosphate kinase (NDPK) and Adenosine-3' 5' cyclic monophosphate cAMP in the pipette solution. RESULTS: (1) GDP beta S could block the changes induced by both high and low concentration of (D-Pen2.5)-enkephalin (DPDPE) (P < 0.05). (2) PTX could inhibit the excitative regulation on K+ channel by high concentration of DPDPE (P < 0.05). But CTX had no effect on K+ channel caused by DPDPE. (3) UDP could block the excitative effect of K+ channel by high concentration of NDPK, while have no changes on the inhibitory effect caused by low concentration of opioid agonists. (4) cAMP took part in the regulation in high concentration of agonist administration (P < 0.05), while no changes for low concentration of agonists. CONCLUSIONS: Dual changes were observed on delayed rectifier potassium channel by agonist treatment on NG108-15 cells. The excitative effect was Gi/o coupled in high concentration of agonist incubation, related to cAMP. While the inhibitory effect was possibly induced by G protein beta gamma subunit directly.

Animals↗

PubMed1989

Rubidium ions and the gating of delayed rectifier potassium channels of frog skeletal muscle.

1. Unitary currents were measured through delayed rectifier potassium channels of frog skeletal muscle, under conditions where either potassium or rubidium ions carried current. 2. Unitary currents were reduced in amplitude when Rb+ was the charge carrier, indicating that Rb+ permeated the channel less readily than did K+. On the other hand permeability ratios (PRb/PK) measured from the change in reversal potential upon ionic substitution were 0.92 for the external and 0.67 for the internal mouth of the channel. 3. Ensemble-averaged currents activated under depolarization along a similarly S-shaped time course whether K+ or Rb+ carried current, though slightly more slowly in Rb+. However, under repolarization to a negative level, tail currents were prolonged about tenfold in Rb+. 4. The duration of channel opening was substantially prolonged in Rb+. The distribution of open times was fitted by a single exponential whether K+ or Rb+ was the charge carrier, indicating a single open state. But the mean open time, averaged over all voltages investigated, was 2.65 times greater in Rb+. 5. The prolongation in Rb+ of tail currents under repolarization was associated with increases in the number of openings per burst and in the number of bursts during each tail. 6. The implications of these results for channel gating are discussed. It is argued that an early step in channel activation is more voltage dependent than later steps.

Action Potentials↗

PubMed2003

[Dual regulation by delta opioid receptor agonists on the delayed rectified potassium channels in NG108-15 cells].

OBJECTIVE: To investigate the dual effects by the delta opioid receptor agonists DPDPE on the delayed rectified potassium channels in NG108-15 cells. METHODS: A series of outward currents were evoked in NG108-15 cells by depolarizing voltage from -50 mV to +80 mV at holding potential of -90 mV. These currents were delayed rectified potassium currents. Relatively selected delta opioid receptor agonists DPDPE of higher and lower concentrations were used to modulate the delayed rectified K+ current in NG108-15 cells. Opioid receptor antagonist Naloxone (NAL) and relatively selected delta opioid receptor antagonist Naltrindole (NTI) were used in the present experiments for the characterization of the actions of opioid receptors. RESULTS: The relatively higher concentrations of delta opioid receptor agonist DPDPE (> or = 10(-6) mol/L) significantly increased the amplitude of the delayed rectified K+ current. On the contrary, the relatively lower concentrations of DPDPE (< or = 10(-12) mol/L) decreased the amplitude of the delayed rectified K+ current (P < 0.05). Furthermore both the increase and decrease were time-dependent. CONCLUSIONS: delta opioid receptor agonist has dual regulatory effects on the delayed rectified potassium channels in NG108-15 cells.

Animals↗

PubMed2001

[Inhibition of voltage-activated outward delayed rectifier potassium channel currents in dorsal root ganglion neurons of rats by lead].

OBJECTIVE: To study the effect of lead on voltage-activated outward delayed rectifier potassium channel currents in acute isolated dorsal root ganglion (DRG) neurons of adult rats. METHODS: Patch clamp technique was employed to record the whole cell of DRG in adult rats. RESULTS: In the experiments, delayed rectifier (IK) potassium currents channel was recorded and activation was voltage-dependent. The threshold concentration of lead (Pb2+) for IK was 1 mumol/L, which reduced potassium current by (8.6 +/- 0.8)%, 4 mumol/L of Pb2+ reduced the current by (38.6 +/- 6.2)%, and 8 mumol/L of Pb2+ reduced the current by (63.0 +/- 5.1)%. The action of lead was rapid and its effect would be reversed rapidly to various extent by washing. CONCLUSION: Higher outward delayed rectifier potassium channel currents, which could be reversed.

Animals↗

PubMed1986

Adrenergic modulation of the delayed rectifier potassium channel in calf cardiac Purkinje fibers.

We have investigated the modulation of the delayed rectifier potassium channel in calf cardiac Purkinje fibers by the neurohormone norepinephrine. We find that 0.5 microM norepinephrine increases this K channel current by a factor of 2.7. A maximal increase of about four was found for concentrations of 1 microM and above. Norepinephrine produced a small (less than 5 mV) and variable shift of the K channel reversal potential toward more negative values. The kinetics of the potassium channel are well described by a two-exponential process, both in the absence and presence of norepinephrine. However, norepinephrine substantially decreases the slower time constant with no significant effect on the fast time constant. Potassium channel activation curves in the presence of norepinephrine are very similar to control curves except at large positive potentials. A simple sequential three-state model for this channel can reproduce these data both with and without norepinephrine. The logarithms of the rate constants derived from this model are quadratic functions of voltage, suggesting the involvement of electric field-induced dipoles in the gating of this channel. Most of the kinetic effects of norepinephrine appear to be on a single rate constant.

Animals↗

PubMed2004

Overexpression of beta2-adrenergic receptors cAMP-dependent protein kinase phosphorylates and modulates slow delayed rectifier potassium channels expressed in murine heart: evidence for receptor/channel co-localization.

The cardiac slow delayed rectifier potassium channel (IKs), comprised of (KCNQ1) and beta (KCNE1) subunits, is regulated by sympathetic nervous stimulation, with activation of beta-adrenergic receptors PKA phosphorylating IKs channels. We examined the effects of 2-adrenergic receptors (beta2-AR) on IKs in cardiac ventricular myocytes from transgenic mice expressing fusion proteins of IKs subunits and hbeta2-ARs. KCNQ1 and beta2-ARs were localized to the same subcellular regions, sharing intimate localization within nanometers of each other. In IKs/B2-AR myocytes, IKs density was increased, and activation shifted in the hyperpolarizing direction; IKs was not further modulated by exposure to isoproterenol, and KCNQ1 was found to be PKA-phosphorylated. Conversely, beta2-AR overexpression did not affect L-type calcium channel current (ICaL) under basal conditions with ICaL remaining responsive to cAMP. These data indicate intimate association of KCNQ1 and beta2-ARs and that beta2-AR signaling can modulate the function of IKs channels under conditions of increased beta2-AR expression, even in the absence of exogenous beta-AR agonist.

Animals↗

PubMed2003

[The role of delayed rectifier potassium channels in the regulation of bronchial smooth muscle tension in asthmatic rats].

OBJECTIVE: To investigate the role of delayed rectifier potassium channels (K(V)) in the regulation of bronchial smooth muscle tension in asthmatic rats and their effects on bronchial reactivity in vitro. METHODS: By using a specific potassium channel blocker, the bronchial contraction induced by spasmogens was observed in normal and asthmatic rats with the isometric tension recording technique. RESULTS: (1) K(V) blocker 4-aminopyridine (4-AP) caused concentration-dependent bronchial contraction in vitro. The concentration-response curve to 4-AP in the asthmatic group showed a left displacement with bigger pD(2) (the negative logarithm of the drug concentration causing 50% of maximal effect, 2.58 +/- 0.07, n = 10, P < 0.001) and no change in E(max) [maximal effect, (32 +/- 5) mg/mg, P > 0.05], compared with pD(2) (2.12 +/- 0.04, n = 10) and E(max) [(31 +/- 6) mg/mg] obtained in the control group; (2) In the control group, pre-treatment with 0.1 mmol/L 4-AP displaced the concentration-response curves to ET-1 and histamine to the left. pD(2) (for ET-1 and histamine) before and after 4-AP treatment was 6.27 +/- 0.38, 5.59 +/- 0.27 and 6.80 +/- 0.47, 6.42 +/- 0.14 respectively (P < 0.01). E(max) before and after 4-AP treatment was (36 +/- 8) mg/mg, (36 +/- 8) mg/mg and (40 +/- 8) mg/mg, (39 +/- 9) mg/mg respectively (P > 0.05); (3) In the asthmatic group, pre-treatment with 0.1 mmol/L 4-AP had no effect on the concentration-response curve to ET-1 and histamine. There was no significant difference (P > 0.05) in pD(2) before (6.51 +/- 0.07, 5.86 +/- 0.14 respectively) and after (6.48 +/- 0.16, 5.96 +/- 0.08 respectively) 4-AP treatment, and in E(max) before [(61 +/- 8) mg/mg, (54 +/- 11) mg/mg respectively] and after [(65 +/- 10) mg/mg, (55 +/- 9) mg/mg respectively] 4-AP treatment. CONCLUSION: The activity of K(V) decreases in bronchial smooth muscle isolated from asthmatic rats compared with that obtained from normal ones. This change may be involved in the bronchial hyperreactivity to some spasmogens in vitro in asthmatic rats.

Animals↗

PubMed2003

The effects of isoflurane on the cardiac slowly activating delayed-rectifier potassium channel in Guinea pig ventricular myocytes.

UNLABELLED: The slowly activating delayed-rectifier potassium current, IKs, is a major outward current responsible for the repolarization of the cardiac action potential (AP). Dysfunction of this channel can lead to AP prolongation, resulting in the long QT syndrome. We hypothesized that anesthetic-induced AP prolongation is caused by inhibition of IKs, in addition to the inhibition of IKr (rapidly activating delayed-rectifier potassium channel current), a condition often found in drug-induced AP prolongation. The whole-cell patch clamp technique was used to study the effects of isoflurane on IKs and IKr recorded from guinea pig single ventricular myocytes. The effect of protein kinase C on IKs inhibition by isoflurane was also investigated. Isoflurane inhibited IKs in a concentration- and temperature-dependent manner. The inhibitory effects of isoflurane at clinically relevant concentrations of 0.3 and 0.6 mM were greater at 22 degrees C than at 36 degrees C. Voltage-dependent activation of IKs was not affected at these concentrations. IKs deactivation kinetics were accelerated by isoflurane at 22 degrees C but not at 36 degrees C. Isoflurane inhibition of IKs was significantly greater than that of IKr. Protein kinase C activation enhanced IKs but did not suppress the inhibitory effect of isoflurane. Our results suggest that IKs inhibition is one of the mechanisms underlying anesthetic-induced AP and QT prolongation. Because most of the ion channel studies on anesthetic effects are conducted at room temperature, the temperature-dependent effect on IKs confirms the importance of anesthetic experiments conducted at physiological temperature. IMPLICATIONS: The effects of a volatile anesthetic, isoflurane, were determined on a cardiac potassium channel current, IKs, a major ionic component underlying the cardiac action potential. The result shows that IKs is significantly inhibited by isoflurane. This may contribute to anesthetic-induced changes in the electrocardiogram, particularly the prolongation of the QT interval.

Action Potentials↗

PubMed1995

Bistability in cerebellar Purkinje cell dendrites modelled with high-threshold calcium and delayed-rectifier potassium channels.

Phase-plane analysis of the ionic currents underlying dendritic plateau potentials was carried out to study the nonlinear dynamics and steady-state transfer properties of the dendritic tree in cerebellar Purkinje cells. The results of an analysis of the P-type calcium and delayed rectifier potassium channel system are presented in this study. These channels constitute a simple system that can support bistability and plateau potentials. By requiring both the steady-state current-voltage curve and nullclines to mimic basic plateau potential properties, we obtained well-defined ranges of specific conductance that can support bistability. Hysteresis was found to be surprisingly prevalent in this simple ion-channel system. Using the steady-state current voltage relationship, we derive concise, algebraic expressions for the voltage and current thresholds of state transitions as functions of specific conductance. The significance of bistability in this ion-channel system is discussed with respect to the generation of plateau potentials in Purkinje cells dendrites and the role of the cerebellum in motor control.

Action Potentials↗

PubMed1993

Single delayed rectifier potassium channels from rabbit coronary artery myocytes.

Cell-attached patches from rabbit coronary artery single smooth muscle cells contained two distinct potassium channel types, namely a large conductance calcium-activated potassium channel and a smaller voltage-activated potassium channel representing the delayed rectifier (IK). When a physiological potassium ion gradient was used, the average slope conductance of single IK channels was 7.26 pS. The time course of activation measured from ensemble averages was well fit by a single exponential raised to the power of 2 and was voltage dependent. Experiments were then performed with potassium (140 mM) on both sides of the membrane to resolve single IK channel currents during deactivation. Ensemble averages of this activity were well described by a two-component exponential, and the time constants were voltage dependent. Mean open times were significantly shorter during deactivation than during activation. Closed time distributions typically had two components. These kinetic characteristics were used in testing various state models for voltage-dependent potassium channels.

Animals↗

PubMed1987

The action of external tetraethylammonium ions on unitary delayed rectifier potassium channels of frog skeletal muscle.

1. We have used single-channel recording to investigate the block by extracellular tetraethylammonium ions (TEA+) of delayed rectifier potassium channels of frog skeletal sarcolemma. 2. TEA+ blocks by reducing the apparent amplitude of unitary currents, without detectable increase in open-level current variance. 3. The block by TEA+ appeared to be 1:1, the fractional current being halved at 5.8 mM and -3 mV. The dissociation constant for the block was voltage dependent, increasing e-fold for a 138 mV depolarization. 4. Activation of delayed rectifier potassium currents is not altered by TEA+. 5. Open times, which in the presence of TEA+ represents bursts of open and blocked events, are not increased by TEA+, indicating that blocked channels are able to close normally.

Action Potentials↗

PubMed1998

The small GTP-binding protein RhoA regulates a delayed rectifier potassium channel.

Tyrosine kinases activated by G protein-coupled receptors can phosphorylate and thereby suppress the activity of the delayed rectifier potassium channel Kv1.2. Using a yeast two-hybrid screen, we identified the small GTP-binding protein RhoA as a necessary component in this process. Coimmunoprecipitation experiments confirmed that RhoA associates with Kv1.2. Electrophysiological analyses revealed that overexpression of RhoA markedly reduced the basal current generated by Kv1.2 expressed in Xenopus oocytes. Furthermore, in 293 cells expressing Kv1.2 and ml muscarinic acetylcholine receptors, inactivating RhoA using C3 exoenzyme blocked the ability of ml receptors to suppress Kv1.2 current. Therefore, these results demonstrate that RhoA regulates Kv1.2 activity and is a central component in the mechanism of receptor-mediated tyrosine kinase-dependent suppression of Kv1.2.

ADP Ribose Transferases↗

PubMed2004

Effects of presenilins and beta-amyloid precursor protein on delayed rectifier potassium channels in cultured rat hippocampal neurons.

AIM: To study the effects of presenilin-1 (PS-1), presenilin-2 (PS-2), and amyloid beta-protein precursor (APP695) on delayed rectifier potassium channels (IK) in the cultured rat hippocampal neurons. METHODS: PS-1, PS-2, and APP695 were transfected into the cultured rat hippocampal neurons by transient transfection techniques. The IK current was observed by the whole cell patch-clamp techniques. RESULTS: IK was increased in cultured rat hippocampal neurons, after transient transfection of PS-1, PS-2, and APP695. IK amplitudes and densities were significantly increased from (1689 +/- 412) pA, (48 +/- 18) pA/pF (mock cells, GFP alone, n=17) to (5565 +/- 1403) pA, (252 +/- 107) pA/pF (PS-1/GFP, n=22, P<0.01), (3804 +/- 1651) pA, (120 +/- 58) pA/pF (PS-2/GFP, n=16, P<0.01), and (4978 +/- 904) pA, (218 +/- 70) pA/pF (APP695, n=22, P<0.01). But PS-1, PS-2, and APP695 did not alter the activation curve of IK (P>0.05). CONCLUSION: Overexpression of PS-1, PS-2, and APP695 increased IK in the cultured rat hippocampal neurons. The upregulation of IK may be related to neuronal apoptosis after PS-1, PS-2, and APP695 were transfected.

Amyloid beta-Protein Precursor↗