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PubMed1999

Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy.

Several families of voltage-gated potassium channels (Kv), including a spectrum of subtypes, are involved in regulating and modifying the integration and transmission of electrical signals in the nervous system. However, the specific patterns of Kv expression in normal or injured dorsal root ganglion (DRG) neurons have not been studied. Previous studies have examined the expression of voltage-gated sodium channels in DRG neurons, and also the selective up- and downregulation of several of these channels following axonal injury to the DRG neurons. In the present study, we used immunocytochemical methods to investigate the expression of Kv channels (Kv1.1, 1.2, 1.3, 1.4, 1.5, 1.6, and 2.1) in DRG cells cultured from control and axotomized adult rats. Kv1.2 and 2.1 immunoreactivity in DRG neurons showed large decreases following axotomy, whereas Kv1.1 and 1.3 showed smaller decreases. Kv1.4 and 1.6 immunostaining were not altered by axotomy, and Kv1.5 immunoreactivity was low in both control and axotomized DRG neurons. These results provide molecular correlates for the expression of multiple K+ currents in normal DRG neurons and indicate that, in relation to changes in sodium channel expression, there are decreases in specific potassium channels following axotomy in these cells. The alterations in K+ and Na+ channel expression following axonal injury may lead to changes in electrical excitability of the DRG neurons, and might contribute to chronic pain syndromes.

Animals↗
PubMed2002

Depolarization induces intersubunit cross-linking in a S4 cysteine mutant of the Shaker potassium channel.

Voltage-gated potassium (K(v)) channels are integral membrane proteins, composed of four subunits, each comprising six (S1-S6) transmembrane segments. S1-S4 comprise the voltage-sensing domain, and S5-S6 with the linker P-loop forms the ion conducting pore domain. During activation, S4 undergoes structural rearrangements that lead to the opening of the channel pore and ion conduction. To obtain details of these structural changes we have used the engineered disulfide bridge approach. For this we have introduced the L361C mutation at the extracellular end of S4 of the Shaker K channel and expressed the mutant channel in Xenopus oocytes. When exposed to mild oxidizing conditions (ambient oxygen or copper phenanthroline), Cys-361 formed an intersubunit disulfide bridge as revealed by the appearance of a dimeric band on Western blotting. As a consequence, the mutant channel suffered a significant loss in conductance (measured by two-electrode voltage clamp). Removal of native cysteines failed to prevent the disulfide formation, indicating that Cys-361 forms a disulfide with its counterpart in the neighboring subunit. The effect was voltage-dependent and occurred during channel activation after Cys-361 has been exposed to the extracellular phase. Although the disulfide bridge reduced the maximal conductance, it caused a hyperpolarizing shift in the conductance-voltage relationship and reduced the deactivation kinetics of the channel. The latter two effects suggest stabilization of the open state of the channel. In conclusion, we report that during activation the intersubunit distance between the N-terminal ends of the S4 segments of the L361C mutant Shaker K channel is reduced.

Amino Acid Substitution↗
PubMed2003

Inhibitory effects of potassium channel blockers on carbachol-induced contraction in rat detrusor muscle.

We present accidental findings that potassium channel blockers, such as tetraethyl-ammonium (TEA) or 4-aminopyridine (4-AP), inhibit the sustained tonic contraction induced by carbachol in rat detrusor muscle strips. The relatively lower concentrations (<2 mM) of TEA and 4-AP inhibited phasic and tonic contractions induced by 5 micro M carbachol, whilst the relatively higher concentrations of TEA and 4-AP (>5 mM) potentiated phasic contractions. The potentiation of phasic contraction was not observed in nicardipine pretreated condition. In nicardipine pretreated condition, the concentration-response curves for the negative inotropic effect of potassium channel blockers were shifted to the right by the increasing concentration of carbachol from 0.5 microM to 5 microM. IC50 was changed significantly from 0.19 to 0.64 mM (TEA) and from 0.21 to 0.96 (4-AP). Such inhibitory effects were also observed in Ca2+ depleted condition, where 0.1 mM EGTA and 1 microM thapsigargin were added into Ca2+ free solution. In conclusion, inhibitory effects of potassium channel blockers on carbachol-induced contraction may be ascribed to the direct inhibition of receptor-agonist binding.

4-Aminopyridine↗
PubMed2000

A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons.

Cerebellar granule neurons (CGNs) are one of the most populous cells in the mammalian brain. They express an outwardly rectifying potassium current, termed a "standing-outward" K(+) current, or IK(SO), which does not inactivate. It is active at the resting potential of CGNs, and blocking IK(SO) leads to cell depolarization. IK(SO) is blocked by Ba(2+) ions and is regulated by activation of muscarinic M(3) receptors, but it is insensitive to the classical broad-spectrum potassium channel blocking drugs 4-aminopyridine and tetraethylammonium ions. The molecular nature of this important current has yet to be established, but in this study, we provide strong evidence to suggest that IK(SO) is the functional correlate of the recently identified two-pore domain potassium channel TASK-1. We show that IK(SO) has no threshold for activation by voltage and that it is blocked by small extracellular acidifications. Both of these are properties that are diagnostic of TASK-1 channels. In addition, we show that TASK-1 currents expressed in Xenopus oocytes are inhibited after activation of endogenous M(3) muscarinic receptors. Finally, we demonstrate that mRNA for TASK-1 is found in CGNs and that TASK-1 protein is expressed in CGN membranes. This description of a functional two-pore domain potassium channel in the mammalian central nervous system indicates its physiological importance in controlling cell excitability and how agents that modify its activity, such as agonists at G protein-coupled receptors and hydrogen ions, can profoundly alter both the neuron's resting potential and its excitability.

Animals↗
PubMed1982

Flurazepam interaction with sodium and potassium channels in squid giant axon.

External application of 0.05-1.0 mM flurazepam was found to partially block both sodium and potassium currents in voltage-clamped squid giant axons. At the same concentration the fractional block of the potassium current was found to be 3 times greater than that of the sodium current. In the presence of the drug the potassium current appeared to "inactivate', as flurazepam block became more profound during the course of the depolarization. The decay of the potassium current can be explained by a model in which flurazepam enters and blocks the potassium channels only after they have opened. Once bound in the potassium channel, removal of flurazepam from its binding site develops slowly (tau = 48 ms). Thus repetitive stimulation of the nerve produced a cumulative block. When applied inside the axon flurazepam was found to be 1.5 (n = 4) times more potent blocker of potassium channels than following external application. This result suggests that when applied externally, a neutral form of the drug diffuses across the membrane and blocks occurs from the inner end of the channel.

Animals↗
PubMed1992

Effects of potassium channel openers and calcium channel blockers on the force responses of the electrically driven rat right ventricle strip.

1. The effects of potassium channel openers (cromakalim and pinacidil) and of calcium channel blockers (verapamil, diltiazem and flunarizine) on the contractile responses of the rat right ventricle have been determined. 2. On the electrically driven rat right ventricle cromakalim at 3 x 10(-7), 10(-6), 3 x 10(-6) M and 10(-5) M, and pinacidil at 10(-6), 10(-5) and 3 x 10(-5) M had no effect on the force responses to cardiac stimulation or to isoprenaline. 3. Pinacidil at 10(-4) M in a vehicle of 0.7% ethanol reduced the force responses to cardiac stimulation. This inhibitory effect was solely due to the ethanol. Pinacidil in 5 x 10(-4) M HCl (which had no effect alone) potentiated some of the responses to isoprenaline. 4. Verapamil, greater than or equal to 10(-6) M, diltiazem, greater than or equal to 10(-5) M, and flunarizine, greater than or equal to 10(-6) M, reduced the force responses to cardiac stimulation and to isoprenaline. 5. The present study has shown that calcium channel blockers, but not potassium channel openers, have inhibitory effects on the rat right ventricle.

Animals↗
PubMed1995

Sympathetic activation, ventricular repolarization and Ikr blockade: implications for the antifibrillatory efficacy of potassium channel blocking agents.

OBJECTIVES: The aim of the present study was to test, in vivo and in vitro, the influence of adrenergic activation on action potential prolongation induced by the potassium channel blocking agent d-sotalol. BACKGROUND: d-Sotalol is not effective against myocardial ischemia-dependent ventricular fibrillation in the presence of elevated sympathetic activity. Most potassium channel blockers, such as d-sotalol, affect only one of the two components of Ik (Ikr) but not the other (Iks). Iks is activated by isoproterenol. An unopposed activation of Iks might account for the loss of anti-fibrillatory effect by d-sotalol in conditions of high sympathetic activity. METHODS: In nine anesthetized dogs we tested at constant heart rate (160 to 220 beats/min) the influences of left stellate ganglion stimulation on the monophasic action potential prolongation induced by d-sotalol. In two groups of isolated guinea pig ventricular myocytes we tested the effect of isoproterenol (10(-9) mol/liter) on the action potential duration at five pacing rates (from 0.5 to 2.5 Hz) in the absence (n = 6) and in the presence (n = 8) of d-sotalol. RESULTS: In control conditions, both in vivo and in vitro, adrenergic stimulation did not significantly change action potential duration. d-Sotalol prolonged both monophasic action potential duration in dogs and action potential duration of guinea pig ventricular myocytes by 19% to 24%. Adrenergic activation, either left stellate ganglion stimulation in vivo or isoproterenol in vitro, reduced by 40% to 60% the prolongation of action potential duration produced by d-sotalol. CONCLUSIONS: Sympathetic activation counteracts the effects of potassium channel blockers on the duration of repolarization and may impair their primary antifibrillatory mechanism. An intriguing clinical implication is that potassium channel blockers may not offer effective protection from malignant ischemic arrhythmias that occur in a setting of elevated sympathetic activity.

Action Potentials↗
PubMed1995

Transmembrane segments critical for potassium channel function.

The relative contribution of the transmembrane segments in the alpha-subunit of Shaker-type potassium channels was investigated in relation to potassium channel function. Starting from a wild-type Kv1.1 channel, four different deletion mutants were made, missing respectively transmembrane segments S1 and S2, S2 and S3, S1 to S3, and S1 to S4. To ensure the assembly of the different subunits, the hydrophylic N-terminal domain was always conserved. The lack of transmembrane segments S1 to S4 converts a depolarization-activated WT Kv1.1 channel with outward rectification into a hyperpolarization-activated channel with inward rectification. In contrast, mutant channels missing transmembrane segments S1 and S2, S2 and S3, or S1 to S3 did not reveal functional expression.

Animals↗
PubMed1994

Potassium channel opener, YM 934, inhibits neurogenic plasma leakage in guinea pig airways.

The effect of a potassium channel opener, YM 934, on neurogenic airway plasma leakage was examined in anesthetized guinea pigs. Airway plasma leakage was evoked by stimulation of both vagal nerves in the presence of atropine (1 mg/kg, intravenous) and propranolol (1 mg/kg, intravenous), and was measured by extravasation of Evans blue dye (30 mg/kg, intravenous) in trachea (Tr), main bronchi (MB), and central (cIPA) and peripheral intrapulmonary airways (pIPA). Vagal stimulation significantly increased the dye leakage in all portions of the airway. YM 934 (10, 30, and 100 micrograms/kg, intravenous) inhibited vagally-induced plasma leakage in Tr, MB, cIPA, and pIPA, and this inhibitory effect of YM 934 was reduced by the ATP-sensitive potassium channel blocker, glibenclamide (25 mg/kg, intravenous). By contrast, YM 934 (100 micrograms/kg, intravenous) had no inhibitory effect on exogenous substance P (0.5 and 1 micrograms/kg, intravenous)-induced plasma leakage in any parts of the airway. These results indicate that YM 934 inhibits airway neurogenic inflammation by modulating the release of neuropeptides from the sensory nerve endings, and that the inhibitory effect can be attributed to the potassium channel opening activity of this compound.

Animals↗
PubMed1998

Effect of diazoxide, an ATP-dependent potassium-channel opener, on isolated aortae of normal and diabetic rats.

1. The effect of diazoxide on the potassium-induced contraction and its inhibitory effect on noradrenaline-induced contraction were studied in the isolated aortic rings of normal and streptozocin-treated diabetic rats. 2. Diazoxide relaxed potassium-induced contraction in normal and diabetic rat aortae. There was no statistically significant difference in the relaxing effect of diazoxide in these two groups of rats. Glibenclamide inhibited the relaxing effect of diazoxide in normal and diabetic rat aortae to the same extent. Pretreatment of tissues with diazoxide prevented the noradrenaline-induced contraction. This inhibitory effect significantly differed between normal and diabetic rats. 3. It is concluded that, in the rat aorta, the state of potassium channels and the potency of diazoxide to open these channels are not affected by experimental diabetes. The observed differences between the responses of normal and diabetic aortae to the inhibitory effect of diazoxide on noradrenaline-induced contraction can be attributed to a mechanism(s) other than potassium-channel opening by diazoxide, which might be modified in diabetes, or to different consequences after potassium-channel opening in diabetic tissues compared with normal tissues.

Animals↗
PubMed1999

Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin.

The structurally defined sea anemone peptide toxins ShK and BgK potently block the intermediate conductance, Ca(2+)-activated potassium channel IKCa1, a well recognized therapeutic target present in erythrocytes, human T-lymphocytes, and the colon. The well characterized voltage-gated Kv1.3 channel in human T-lymphocytes is also blocked by both peptides, although ShK has a approximately 1,000-fold greater affinity for Kv1.3 than IKCa1. To gain insight into the architecture of the toxin receptor in IKCa1, we used alanine-scanning in combination with mutant cycle analyses to map the ShK-IKCa1 interface, and compared it with the ShK-Kv1.3 interaction surface. ShK uses the same five core residues, all clustered around the critical Lys(22), to interact with IKCa1 and Kv1.3, although it relies on a larger number of contacts to stabilize its weaker interactions with IKCa1 than with Kv1.3. The toxin binds to IKCa1 in a region corresponding to the external vestibule of Kv1.3, and the turret and outer pore of the structurally defined bacterial potassium channel, KcsA. Based on the NMR structure of ShK, we deduce the toxin receptor in IKCa1 to have x-y dimensions of approximately 22 A, a diameter of approximately 31 A, and a depth of approximately 8 A; we estimate that the ion selectivity lies approximately 13 A below the outer lip of the toxin receptor. These dimensions are in good agreement with those of the KcsA channel determined from its crystal structure, and the inferred structure of Kv1.3 based on mapping with scorpion toxins. Thus, these distantly related channels exhibit architectural similarities in the outer pore region. This information could facilitate development of specific and potent modulators of the therapeutically important IKCa1 channel.

Amino Acid Sequence↗
PubMed1994

Cardiovascular profile of RWJ 29009, a new potassium channel activator, in anesthetized and conscious dogs.

RWJ-29009, (6S)-trans(-)-1-(6,7-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-5 H-thieno[3,2-b]pyran-7-yl)-2-piperidinone, is a structurally novel and extremely potent potassium channel activator that may be useful for treatment of hypertension and ischemic heart disease. We assessed the cardiovascular profile of RWJ 29009 in anesthetized and conscious dogs. RWJ 29009 (0.1-2 micrograms/kg intravenously, i.v.) dose-relatedly increased coronary blood flow (CBF) and decreased arterial pressure in anesthetized dogs. Total peripheral resistance and coronary vascular resistance were concurrently reduced without significant changes in heart rate (HR) or cardiac output (CO). Left ventricular (LV) dP/dtmax and myocardial contractile force were decreased only at the highest dose of 10 micrograms/kg. Cromakalim (3-100 micrograms/kg), although much less potent, had a qualitatively similar profile. Glyburide pretreatment (5 mg/kg i.v.) shifted the dose response of RWJ 29009 for increasing CBF and decreasing arterial pressure to the right. The dose responses of cromakalim were similarly shifted to the right, whereas the effects of nifedipine on CBF and arterial pressure were not affected by glyburide. RWJ 29009 (0.3 and 1 microgram/kg) had no effect on myocardial O2 consumption (MVO2) except for a transient increase immediately after administration of 1 microgram/kg. MVO2 returned to control 15 min after dosing, although CBF remained significantly increased. In conscious dogs, RWJ 29009 (0.3-10 micrograms/kg, i.v. and orally, p.o.) produced dose-related increases in CBF and decreases in arterial pressure similar to those produced in anesthetized dogs, except that HR was increased concurrently. The i.v. and p.o. potency of RWJ 29009 were comparable, indicating high oral bioavailability. Thus, RWJ 29009 is an extremely potent coronary and peripheral vasodilator with a cardiovascular profile similar to that of other potassium channel activators. Like those of other potassium channel activators, its mechanism of action appears to involve activation of ATP-regulated potassium channels.

Administration, Oral↗
PubMed2001

Mechanism underlying slow kinetics of the OFF gating current in Shaker potassium channel.

Based on the structure of the KcsA potassium channel, the Shaker K+ channel is thought to have, near the middle of the membrane, a cavity that can be occupied by a permeant or a blocking cation. We have studied the interaction between cations in the cavity and the activation gate of the channel, using a set of monovalent cations together with Shaker mutants that modify the structure of the cavity. Our results show that reducing the size of the side chain at position 470 makes it possible for the mutant channel, unlike native Shaker, to close with tetraethylammonium (TEA+) or the long-chain TEA-derivative C10+ trapped inside the channel. Neither I470 mutants nor Shaker can close when N-methyl-glucamine (NMG+) is in the channel, even though this ion is smaller than C10+. Apparently, the carbohydrate side chain of NMG+ prevents gate closing. Gating currents recorded from Shaker and I470C were measured in the presence of different intracellular cations to further analyze the interaction of cations with the gate. Our results suggest that the cavity in Shaker is so small that even permeant cations like Rb+ or Cs+ must leave the cavity before the channel gate can close.

Alanine↗
PubMed2000

The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK.

The mitogen-activated protein kinase ERK has recently become a focus of studies of synaptic plasticity and learning and memory. Due to the prominent role of potassium channels in regulating the electrical properties of membranes, modulation of these channels by ERK could play an important role in mediating learning-related synaptic plasticity in the CNS. Kv4.2 is a Shal-type potassium channel that passes an A-type current and is localized to dendrites and cell bodies in the hippocampus. The sequence of Kv4.2 contains several consensus sites for ERK phosphorylation. In the present studies, we tested the hypothesis that Kv4.2 is an ERK substrate. We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). We used this information to develop antibodies that recognize Kv4.2 phosphorylated by ERK2. One of our phospho-site-selective antibodies was generated using a triply phosphorylated peptide as the antigen. We determined that this antibody recognizes ERK-phosphorylated Kv4.2 in COS-7 cells transfected with Kv4.2 and native ERK-phosphorylated Kv4.2 in the rat hippocampus. These observations indicate that Kv4.2 is a substrate for ERK in vitro and in vivo, and suggest that ERK may regulate potassium-channel function by direct phosphorylation of the pore-forming alpha subunit.

Amino Acid Sequence↗
PubMed2001

A discrete amino terminal domain of Kv1.5 and Kv1.4 potassium channels interacts with the spectrin repeats of alpha-actinin-2.

The interaction between the amino terminus of Kv1-type potassium channels and alpha-actinin-2 has been investigated. Using a combination of yeast two-hybrid analysis and in vitro binding assays, alpha-actinin-2 was found to bind to the N-termini of both Kv1.4 and Kv1.5 but not to the equivalent segments of Kv1.1, Kv1.2 or Kv1.3. Deletion analysis in the in vitro binding assays delineated the actinin binding region of Kv1.5 to between amino acids 73 and 148 of the channel. The Kv1.5 binding sites in alpha-actinin-2 were found to lie within actinin's internal spectrin repeats. Unlike the reported interaction between actinin and the NMDA receptor, calmodulin was found to have no effect on actinin binding to Kv1.5.

Actinin↗
PubMed2004

Potassium channels and pain: present realities and future opportunities.

Four families of potassium channels with different structures, functional characteristics and pharmacological sensitivity, are distinguished in neurons: voltage-gated (K(v)), calcium-activated (K(Ca)), inward rectifier (K(ir)) and two-pore (K(2P)) K(+) channels. During the last 15 years, numerous studies have demonstrated that the opening of some of these K(+) channels plays an important role in the antinociception induced by agonists of many G-protein-coupled receptors (alpha(2)-adrenoceptors, opioid, GABA(B), muscarinic M(2), adenosine A(1), serotonin 5-HT(1A) and cannabinoid receptors), as well as by other antinociceptive drugs (nonsteroidal antiinflammatory drugs [NSAIDs], tricyclic antidepressants, etc.) and natural products. Several specific types of K(+) channels are involved in antinociception. The most widely studied are the ATP-sensitive K(+) channels (K(ATP)), members of the K(ir) family, which participate in the antinociception induced by many drugs that activate them in both the central and the peripheral nervous system. The opening of G-protein-regulated inwardly rectifying K(+) channels (GIRK or K(ir)3), K(v)1.1 and two types of K(Ca) channels, the small- and large-conductance calcium-activated K(+) channels (SK and BK channels, respectively), also play a role in the antinociceptive effect of different drugs and natural products. Recently, drugs that open K(+) channels by direct activation (such as openers of neuronal K(v)7 and K(ATP) channels) have been shown to produce antinociception in models of acute and chronic pain, which suggests that other neuronal K(+) channels (e.g. K(v)1.4 channels) may represent an interesting target for the development of new K(+) channel openers with antinociceptive effects.

Analgesics, Non-Narcotic↗
PubMed1998

Slob, a novel protein that interacts with the Slowpoke calcium-dependent potassium channel.

Slob, a novel protein that binds to the carboxy-terminal domain of the Drosophila Slowpoke (dSlo) calcium-dependent potassium channel, was identified with a yeast two-hybrid screen. Slob and dSlo coimmunoprecipitate from Drosophila heads and heterologous host cells, suggesting that they interact in vivo. Slob also coimmunoprecipitates with the Drosophila EAG potassium channel but not with Drosophila Shaker, mouse Slowpoke, or rat Kv1.3. Confocal fluorescence microscopy demonstrates that Slob and dSlo redistribute in cotransfected cells and are colocalized in large intracellular structures. Direct application of Slob to the cytoplasmic face of detached membrane patches containing dSlo channels leads to an increase in channel activity. Slob may represent a new class of multi-functional channel-binding proteins.

Amino Acid Sequence↗
PubMed2005

Protein kinase C bound with A-kinase anchoring protein is involved in muscarinic receptor-activated modulation of M-type KCNQ potassium channels.

The second messenger for closure of M/KCNQ potassium channels in post-ganglionic neurons and central neurons had remained as a 'mystery in the neuroscience field' for over 25 years. However, recently the details of the pathway leading from muscarinic acetylcholine receptor (mAChR)-stimulation to suppression of the M/KCNQ-current were discovered. A key molecule is A-kinase anchoring protein (AKAP; AKAP79 in human, or its rat homolog, AKAP150) which forms a trimeric complex with protein kinase C (PKC) and KCNQ channels. AKAP79 or 150 serves as an adapter that brings the anchored C-kinase to the substrate KCNQ channel to permit the rapid and 'definitive' phosphorylation of serine residues, resulting in avoidance of signal dispersion. Thus, these findings suggest that mAChR-induced short-term modulation (or memory) does occur within the already well-integrated molecular complex, without accompanying Hebbian synapse plasticity. However, before this identity is confirmed, many other modulators which affect M-currents remain to be addressed as intriguing issues.

A Kinase Anchor Proteins↗