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At least 217 records · Page 12Linked to original sources
PubMed2000

Dendritic potassium channels in hippocampal pyramidal neurons.

Potassium channels located in the dendrites of hippocampal CA1 pyramidal neurons control the shape and amplitude of back-propagating action potentials, the amplitude of excitatory postsynaptic potentials and dendritic excitability. Non-uniform gradients in the distribution of potassium channels in the dendrites make the dendritic electrical properties markedly different from those found in the soma. For example, the influence of a fast, calcium-dependent potassium current on action potential repolarization is progressively reduced in the first 150 micrometer of the apical dendrites, so that action potentials recorded farther than 200 micrometer from the soma have no fast after-hyperpolarization and are wider than those in the soma. The peak amplitude of back-propagating action potentials is also progressively reduced in the dendrites because of the increasing density of a transient potassium channel with distance from the soma. The activation of this channel can be reduced by the activity of a number of protein kinases as well as by prior depolarization. The depolarization from excitatory postsynaptic potentials (EPSPs) can inactivate these A-type K+ channels and thus lead to an increase in the amplitude of dendritic action potentials, provided the EPSP and the action potentials occur within the appropriate time window. This time window could be in the order of 15 ms and may play a role in long-term potentiation induced by pairing EPSPs and back-propagating action potentials.

Action Potentials↗
PubMed1989

Isolation of a cDNA clone coding for a putative second potassium channel indicates the existence of a gene family.

A putative second potassium channel expressed in rat brain is identified by cloning and characterization of cDNA clones. Two cDNA clones, isolated from rat brain libraries, encode a 499-residue protein that is 80% identical with a previously described rat brain potassium channel and 68% identical with a Drosophila potassium channel. This new potassium channel is called BK2 to distinguish it from the previously described potassium channel (BK1). The BK2 gene, unlike the Drosophila potassium channel gene complex, appears to produce a single, large (approximately 9.5-kilobase) RNA transcript. Southern analysis of rat genomic DNA indicates that the BK1 and BK2 transcripts are the products of independent genes. Analysis of the distribution of BK2 transcripts in rat brain by in situ hybridization histochemistry suggests that the BK2 gene is ubiquitously expressed by central nervous system neurons. Identification of this putative second mammalian potassium channel cDNA indicates the existence of a potassium channel gene family, confirming electrophysiological data on the diversity of potassium channels expressed in rat brain.

Amino Acid Sequence↗
PubMed1995

Role of potassium channels in cerebral blood vessels.

BACKGROUND: Hyperpolarization of vascular muscle in response to activation of potassium channels is a major mechanism of vasodilatation. In cerebral blood vessels, four different potassium channels have been described: ATP-sensitive potassium channels, calcium-activated potassium channels, delayed rectifier potassium channels, and inward rectifier potassium channels. SUMMARY OF REVIEW: Activation of ATP-sensitive and calcium activated potassium channels appears to play a major role in relaxation of cerebral arteries and arterioles in response to diverse stimuli, including receptor-mediated agonists, intracellular second messengers, and hypoxia. Both calcium-activated and delayed rectifier potassium channels may contribute to a negative feedback system that regulates tone in large cerebral arteries. The influence of ATP-sensitive and calcium-activated potassium channels is altered in disease states such as hypertension, diabetes, and atherosclerosis. CONCLUSIONS: Activation of potassium channels is a major mechanism of cerebral vasodilatation. Alteration of activity of potassium channels and impairment of vasodilatation may contribute to the development or maintenance of cerebral ischemia or vasospasm.

Adenosine Triphosphate↗
PubMed2003

MinK-related peptide 2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain.

Delayed rectifier potassium current diversity and regulation are essential for signal processing and integration in neuronal circuits. Here, we investigated a neuronal role for MinK-related peptides (MiRPs), membrane-spanning modulatory subunits that generate phenotypic diversity in cardiac potassium channels. Native coimmunoprecipitation from rat brain membranes identified two novel potassium channel complexes, MiRP2-Kv2.1 and MiRP2-Kv3.1b. MiRP2 reduces the current density of both channels, slows Kv3.1b activation, and slows both activation and deactivation of Kv2.1. Altering native MiRP2 expression levels by RNAi gene silencing or cDNA transfection toggles the magnitude and kinetics of endogenous delayed rectifier currents in PC12 cells and hippocampal neurons. Computer simulations predict that the slower gating of Kv3.1b in complexes with MiRP2 will broaden action potentials and lower sustainable firing frequency. Thus, MiRP2, unlike other known neuronal beta subunits, provides a mechanism for influence over multiple delayed rectifier potassium currents in mammalian CNS via modulation of alpha subunits from structurally and kinetically distinct subfamilies.

Action Potentials↗
PubMed2001

Initial isolation and analysis of the human Kv1.7 (KCNA7) gene, a member of the voltage-gated potassium channel gene family.

A novel human potassium channel gene was identified and isolated. The maximal open reading frame encodes a protein of 456 amino acids. The predicted product exhibits 91% amino acid identity to the murine voltage-gated potassium channel protein Kv1.7 (Kcna7), which plays an important role in the repolarization of cell membranes. Based on the high similarity, the human gene has been classified as the ortholog of the mouse Kcna7 and given the name Kv1.7 (KCNA7). A structural prediction identified a pore region characteristic of potassium channels and six membrane-spanning domains. Northern expression analysis revealed the gene is expressed preferentially in skeletal muscle, heart and kidney. However, it is expressed at lower level in other tissues, including liver. A single mRNA isoform was observed, with a size of approximately 4.5 kb. Using fluorescence in situ hybridization, the gene was mapped to chromosomal band 19q13.4 (269.13 cR(3000)). A genomic sequence was identified in the database from this region, and the KCNA7 gene structure determined. Computational analysis of the genomic sequence reveals the location of a putative promoter and a likely muscle-specific regulatory region. Initial comparison to the published murine Kcna7 cDNA suggested a different N-terminal sequence for the human protein, however, further analysis suggests that the original mouse sequence contained an error or an unusual polymorphism.

Amino Acid Sequence↗
PubMedDate not supplied

[New activators of potassium channels: design, pharmacology and therapeutic perspectives].

Potassium channels (K+ channels) constitute the most diverse group of ionic channels. One of them, the ATP-sensitive K+ channel (KATP channel), was identified in numerous tissues (smooth muscle, pancreatic B-cells, central nervous system,...). This channel is of particular interest for us since we have developed various pharmacological models for the study of new potassium channel openers. Among those, diazoxide (a benzothiadiazine dioxide) is an interesting reference compound since its biological activity was observed with comparable intensity on the vascular tissue (smooth muscle) as well as on the pancreatic tissue (endocrine tissue). One of our aims was the preparation of original pyridinic analogues of diazoxide (pyridothiadiazinedioxides) and their evaluation as potassium channel openers in order to show a tissue selectivity different from that of diazoxide. Indeed, therapeutic perspectives of potassium channel openers will depend upon the discovery of new classes of compounds exhibiting an effective tissue selectivity.

Animals↗
PubMed2001

Distribution of the messenger RNA for the small conductance calcium-activated potassium channel SK3 in the adult rat brain and correlation with immunoreactivity.

Small conductance calcium-activated potassium channels are voltage independent potassium channels which modulate the firing patterns of neurons by activating the slow component of the afterhyperpolarization. The genes encoding a family of small conductance calcium-activated potassium channels have been cloned and up to now three known members have been described and named small conductance calcium-activated potassium channel type 1, small conductance calcium-activated potassium channel type 2 and small conductance calcium-activated potassium channel type 3; the distribution of their messenger RNA in the rat CNS has already been performed but only in a limited detail. The present study represents the first detailed analysis of small conductance calcium-activated potassium channel type 3 mRNA distribution in the adult rat brain and resulted in a strong to moderate expression of signal in medial habenular nucleus, substantia nigra compact part, suprachiasmatic nucleus, ventral tegmental area, lateral septum, dorsal raphe and locus coeruleus. Immunohistological experiments were also performed and confirmed the presence of small conductance calcium-activated potassium channel type 3 protein in medial habenular nucleus, locus coeruleus and dorsal raphe. Given the importance of dorsal raphe, locus coeruleus and substantia nigra/ventral tegmental area for serotonergic, noradrenergic and dopaminergic transmission respectively, our results pose the morphological basis for further studies on the action of small conductance calcium-activated potassium channel type 3 in serotonergic, noradrenergic and dopaminergic transmission.

Animals↗
PubMed1997

A human intermediate conductance calcium-activated potassium channel.

An intermediate conductance calcium-activated potassium channel, hIK1, was cloned from human pancreas. The predicted amino acid sequence is related to, but distinct from, the small conductance calcium-activated potassium channel subfamily, which is approximately 50% conserved. hIK1 mRNA was detected in peripheral tissues but not in brain. Expression of hIK1 in Xenopus oocytes gave rise to inwardly rectifying potassium currents, which were activated by submicromolar concentrations of intracellular calcium (K0.5 = 0.3 microM). Although the K0.5 for calcium was similar to that of small conductance calcium-activated potassium channels, the slope factor derived from the Hill equation was significantly reduced (1.7 vs. 3. 5). Single-channel current amplitudes reflected the macroscopic inward rectification and revealed a conductance level of 39 pS in the inward direction. hIK1 currents were reversibly blocked by charybdotoxin (Ki = 2.5 nM) and clotrimazole (Ki = 24.8 nM) but were minimally affected by apamin (100 nM), iberiotoxin (50 nM), or ketoconazole (10 microM). These biophysical and pharmacological properties are consistent with native intermediate conductance calcium-activated potassium channels, including the erythrocyte Gardos channel.

Amino Acid Sequence↗
PubMed2006

hERG potassium channels and cardiac arrhythmia.

hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.

Animals↗
PubMed1984

Single channel recordings of calcium-activated potassium channels in the apical membrane of rabbit cortical collecting tubules.

Recordings of single potassium channels from the apical membrane of rabbit cortical collecting tubule have been achieved using the patch-clamp technique. The conductive properties of the channel have been studied in inside-out patches. The slope conductance of the open channel is approximately equal to 90 pS. The channel is selective to potassium over sodium, with a selectivity ratio of 9:1. Decreasing the calcium concentration of the solution bathing the cytoplasmic face of the patch results in a decrease of the open-channel probability. Decreasing the calcium concentration to 10 nM or less completely inhibited channel activity. The channel is also inhibited by barium in a dose-dependent fashion.

Animals↗
PubMed2004

Maturation of spiking activity in trout retinal ganglion cells coincides with upregulation of Kv3.1- and BK-related potassium channels.

Developmental changes in membrane excitability and the potassium channel profile were monitored in acutely isolated trout retinal ganglion cells by patch-clamp recording in combination with single-cell RT-PCR. During embryonic development in the egg, a sustained above-threshold stimulation of ganglion cells elicited in most cases only a single spike response. After hatching, the proportion of multiply spiking cells increased strongly and the ability of spike frequency coding was acquired. This was accompanied by the occurrence of a highly tetraethylammonium (TEA)- and quinine-sensitive delayed rectifier current, which gradually masked a rapidly inactivating A-type potassium current that was predominant at earlier stages. Pharmacology of the delayed rectifier current closely matched those of recombinant Traw1, a Kv3.1-related potassium channel in trout. The appearance of this current correlated closely with initial expression of Traw1 and Traw2 channel transcripts, as revealed by multiplex single-cell RT-PCR, whereas mRNA, encoding Shaker-related channel genes in trout (termed Tsha1-Tsha4), were already detectable at early embryonic stages. Iberiotoxin-sensitive, calcium-activated potassium currents (BK) were extremely low before hatching, but increased significantly thereafter. These developmental changes in potassium channel expression occurred after the arrival of retinal fibers in the optic tectum and the initiation of synapse formation in the visual center. It is suggested that early expressed Shaker-related potassium channels could act to influence neuronal differentiation, whereas proper neuronal signaling requires expression of Kv3.1- and BK-related potassium channels.

Aging↗
PubMed1990

Modulation of ATP-sensitive K+ channel activity and contractile behavior in mammalian ventricle by the potassium channel openers cromakalim and RP49356.

We have investigated the effects of potassium channel opening drugs on the ATP-dependence of ATP-sensitive K+ channel activity and on contractile activity in rat and guinea pig ventricular myocytes. The results show that cromakalim (BRL34915), and RP49356, agents reported to open ATP-sensitive K+ channels, do so by shifting the intracellular [ATP] required to cause half-maximal inhibition of channel activity (ki) to higher [ATP]. In guinea pig ventricular myocytes at 37 degrees C, the ki was shifted from 79 to 152 microM by 40 microM cromakalim and, in rat myocytes at room temperature, the ki was also shifted to higher [ATP] by 50 microM RP49356. The effect of externally applied RP49356 on the contractile activity of intact rat ventricular myocytes was investigated. At 100 microM the drug was without effect in the presence of normal bathing solution containing 10 mM glucose. When glucose in the bathing medium had been replaced by 2-deoxyglucose for 84 +/- 2 min, 100 microM RP49356 decreased the twitch amplitude to 23 +/- 4% of control. The negative inotropic effect of 100 microM RP49356 increased with time after perfusion with 2-deoxyglucose, and the negative inotropic effect diminished on reperfusing with glucose; 83 +/- 3 min after reperfusing with glucose, twitch amplitude was decreased by only 52 +/- 6% on exposure to 100 microM RP49356. These results suggest that the effect of the potassium channel opening drugs on contractility and electrical behavior will depend critically on the intracellular [ATP]. The results provide an explanation of how potassium channel openers may become clinically useful as cardioprotective agents without interfering with normal function.

Adenosine Triphosphate↗
PubMed2001

Opening of mitochondrial ATP-sensitive potassium channels enhances cardioplegic protection.

BACKGROUND: Mitochondrial and sarcolemmal ATP-sensitive potassium channels have been implicated in cardioprotection; however, the role of these channels in magnesium-supplemented potassium (K/Mg) cardioplegia during ischemia or reperfusion is unknown. METHODS: Rabbit hearts (n = 76) were used for Langendorff perfusion. Sham hearts were perfused for 180 minutes. Global ischemia hearts received 30 minutes of global ischemia and 120 minutes of reperfusion. K/Mg hearts received cardioplegia before ischemia. The role of ATP-sensitive potassium channels in K/Mg cardioprotection during ischemia and reperfusion was investigated, separately using the selective mitochondrial ATP sensitive potassium and channel blocker, 5-hydroxydecanoate, and the selective sarcolemmal ATP-sensitive potassium channel blocker HMR1883. Separate studies were performed using the selective mitochondrial ATP-sensitive potassium channel opener, diazoxide, and the nonselective ATP-sensitive potassium channel opener pinacidil. RESULTS: Infarct size was 1.9%+/-0.4% in sham, 3.7%+/-0.5% in K/Mg, and 27.8%+/-2.4% in global ischemia hearts (p < 0.05 versus K/Mg). Left ventricular peak-developed pressure (percent of equilibrium) at the end of 120 minutes of reperfusion was 91%+/-6% in sham, 92% +/-2% in K/Mg, and 47%+/-6% in global ischemia (p < 0.05 versus K/Mg). Blockade of sarcolemmal ATP-sensitive potassium channels in K/Mg hearts had no effect on infarct size or left ventricular peak-developed pressure. However, blockade of mitochondrial ATP-sensitive potassium channels before ischemia significantly increased infarct size to 23%+/-2% in K/Mg hearts (p < 0.05 versus K/Mg; no statistical significance [NS] as compared to global ischemia) and significantly decreased left ventricular peak-developed pressure to 69%+/-4% (p < 0.05 versus K/Mg). Diazoxide when added to K/Mg cardioplegia significantly decreased infarct size to 1.5%+/-0.4% (p < 0.05 versus K/Mg). CONCLUSIONS: The cardioprotection afforded by K/Mg cardioplegia is modulated by mitochondrial ATP-sensitive potassium channels. Diazoxide when added to K/Mg cardioplegia significantly reduces infarct size, suggesting that the opening of mitochondrial ATP-sensitive potassium channels with K/Mg cardioplegic protection would allow for enhanced myocardial protection in cardiac operations.

Adenosine Triphosphate↗
PubMedDate not supplied

[Potassium channel activators: from pharmacology to therapeutics].

Potassium channels activators (PCA) are drugs which open or prolong the open state duration of potassium channels. Hence they promote potassium efflux, hyperpolarize the cell membrane, thus preventing intracellular penetration of calcium through the voltage-dependent calcium channels. The resulting decrease in intracellular free calcium concentration induces relaxant effects in smooth muscle cells (vessels, bronchi, bladder, etc.) which are the rationale for the present and future therapeutic indications of PCA, namely hypertension, asthma, etc. In animals, PCA produce vasodilating, hypotensive and antihypertensive effects, accompanied by tachycardia and stimulation of the renin-angiotensin system. The regional vasodilator profile of PCA is heterogeneous and their hypotensive properties are antagonized only by glibenclamide, an antagonist of ATP-dependent potassium channels. In patients, only pinacidil, minoxidil and diazoxide are presently used as antihypertensive drugs.

Antihypertensive Agents↗
PubMed1989

Molecular properties of potassium channels.

The paper describes the molecular pharmacology and biochemistry of three types of K+ channels, the calcium-activated potassium channels, ATP-regulated potassium channels and voltage-sensitive potassium channels.

Adenosine Triphosphate↗
PubMed2000

The polar T1 interface is linked to conformational changes that open the voltage-gated potassium channel.

Kv voltage-gated potassium channels share a cytoplasmic assembly domain, T1. Recent mutagenesis of two T1 C-terminal loop residues implicates T1 in channel gating. However, structural alterations of these mutants leave open the question concerning direct involvement of T1 in gating. We find in mammalian Kv1.2 that gating depends critically on residues at complementary T1 surfaces in an unusually polar interface. An isosteric mutation in this interface causes surprisingly little structural alteration while stabilizing the closed channel and increasing the stability of T1 tetramers. Replacing T1 with a tetrameric coiled-coil destabilizes the closed channel. Together, these data suggest that structural changes involving the buried polar T1 surfaces play a key role in the conformational changes leading to channel opening.

Amino Acid Substitution↗
PubMed2004

[High throughput screening method of potassium channel regulators].

AIM: To discover new regulators of potassium channel, an in vitro assay based on DiBAC4 (3) to determine the fluorescence was established for high throughput screening. METHODS: A cell-based 96-well format fluorescence assay using DiBAC4 (3) in cultured PC12 cells was described. Cells were loaded with 5 mumol.L-1 DiBAC4 (3) and incubated at 37 degrees C for 30 min before adding KCl or several known potassium channel regulators. The cellular DiBAC4 (3) fluorescence responce was then detected. The fluorescence changes can be used to evaluate membrane potential changes, which are determined mainly by potassium channels. RESULTS: Extracellular high K(+)-induced depolarization and several potassium channel blockers including 4-AP, TEA, E-4031, glibenclamide, quinidine and nifedipine all evoked increases in DiBAC4 (3) fluorescence response. The potassium channel opener, cromakalim, evoked decrease in DiBAC4 (3) fluorescence response. The fluorescence changes of 4-AP, TEA, glibenclamide, nifedipine and cromakalim were in a concentration-dependent manner. In 76 compounds screened by using the established DiBAC4 (3)-based assay, 9 compounds were found to change the fluorescence dose-dependently. Patch clamp technique is needed to further testify and screen their actions on potassium currents. CONCLUSION: The DiBAC4 (3)-based assay is easily operated, economical and repeatable. So, it can be performed by high throughput screening for potassium channel regulators.

4-Aminopyridine↗
PubMed1985

Differences between mammalian ventral and dorsal spinal roots in response to blockade of potassium channels during maturation.

Differences in potassium channel organization between motor and sensory fibres have been described in amphibians but have not previously been examined in mammals. In the present investigation, we studied whole nerve and single axon responses following pharmacological blockade of potassium conductance in rat ventral and dorsal spinal roots during maturation. Our results indicate a differential sensitivity in maturing mammalian motor and sensory fibres which is most apparent in younger roots. Specifically, application of 4-aminopyridine (4-AP) results in a broadening of the compound action potential in ventral roots which is associated with a delayed repolarization of the individual action potential of single fibres. In contrast, blockade of potassium channels in young dorsal roots results in a late negativity in the compound response which is correlated with multispike bursting activity recorded from single sensory fibres. The effects of 4-AP on ventral root fibres diminish earlier in the course of maturation than do the effects of 4-AP in dorsal root fibres. These results demonstrate developmental differences in the functional organization of potassium channels in mammalian motor and sensory axons which may have implications for differences in coding properties between these two classes of axons.

Action Potentials↗