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At least 109 records · Page 6Linked to original sources
PubMed2000

Molecular evidence for a role of Shaw (Kv3) potassium channel subunits in potassium currents of dog atrium.

We previously described an ultrarapid delayed rectifier current in dog atrial myocytes (IKur,d) with properties resembling currents reported for Kv3.1 channels in neural tissue; however, there was no direct molecular evidence for Shaw subfamily (Kv3) subunit expression in the heart. To identify the molecular basis of IKur,d, we cloned a full-length cDNA (dKv3.1) from canine atrium with homology-based reverse transcription (RT)- polymerase chain reaction (PCR) cloning techniques. A 1755 bp full-length cDNA (dKv3.1) was obtained, with 94.2 % homology to rat brain Kv3.1 (rbKv3.1). The deduced amino acid sequence had 99.3 % homology with rbKv3.1. Heterologous expression of dKv3.1 in Xenopus oocytes produced currents with activation voltage dependence, rectification, and activation and deactivation kinetics that strongly resemble native IKur,d. Like IKur,d, dKv3.1 was found to be highly sensitive to extracellular 4-aminopyridine (4-AP) and tetraethylammonium (TEA). RNase protection assays, Western blots and immunohistochemical studies demonstrated the presence of dKv3.1 transcripts and proteins in dog atrial preparations and isolated canine atrial myocytes. Protein corresponding to the Kv1.5 subunit, which can also carry ultrarapid delayed rectifier current, was absent. Unlike neural tissues, which express two splice variants (Kv3.1a and Kv3.1b), canine atrium showed only Kv3.1b transcripts. Whole-cell patch-clamp studies showed that IKur,d is absent in canine ventricular myocytes, and immunohistochemical and Western blot analysis demonstrated the absence of dKv3.1 protein in canine ventricle. We conclude that the Shaw-type channel dKv3.1 is present in dog atrium, but not ventricle, and is the likely molecular basis of canine atrial IKur,d.

4-Aminopyridine↗
PubMed2003

Phylogenomic analysis and evolution of the potassium channel gene family.

Potassium channels govern the permeability of cells to potassium ions, thereby controlling the membrane potential. In metazoa, potassium channels are encoded by a large, diverse gene family. Previous analyses of this gene family have focused on its diversity in mammals. Here we have pursued a more comprehensive study in Caenorhabditis elegans, Drosophila melanogaster, and mammalian genomes. The investigation revealed 164 potassium channel encoding genes in C. elegans, D. melanogaster, and mammals, classified into seven conserved families, which we applied to phylogenetic analysis. The trees are discussed in relation to the assignment of orthologous relationships between genes and vertebrate genome duplication.

Animals↗
PubMed1994

Cloning and characterization of human and mouse homologs of the Drosophila calcium-activated potassium channel gene, slowpoke.

Potassium channels play important roles in a wide variety of physiological processes. Although several genes encoding voltage-activated potassium channels have been analyzed at the molecular level, no calcium-activated potassium channel gene has yet been characterized in humans. In an effort to provide the foundation for functional analysis of such polypeptides we report the cloning of mouse and human homologs of the Drosophila melanogaster calcium-activated potassium channel gene, slowpoke. Both the human and mouse genes encode polypeptides that have more than 50% amino acid identifies with their Drosophila counterpart. In addition, like the Drosophila slowpoke gene, both the mouse and human genes generate multiple transcripts by alternative splicing. The human gene maps to chromosome 10 based on the results of polymerase chain reaction analysis of genomic DNA from human-hamster hybrid cell lines. Because calcium-activated potassium channels participate in wide variety of cellular functions including neuromuscular communication, secretion and cellular immunity, their continued analysis promises to have broad biological and medical significance.

Amino Acid Sequence↗
PubMed1999

Developmental seizure susceptibility of kv1.1 potassium channel knockout mice.

Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 alpha-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (-/-, +/-, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 -/- animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/- mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1. 1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.

Animals↗
PubMed1990

How might the diversity of potassium channels be generated?

Potassium channels are a diverse group of ion channels present in most eukaryotic cells that have been examined. Over 30 different potassium channels have been characterized biophysically. They show different sensitivities to voltage and/or intracellular messengers, and have different kinetic or pharmacological properties. The wide range of potassium channel properties reflects the broad spectrum of cellular functions that they serve, including control of synaptic efficacy, of heart beat, and of endocrine and exocrine secretion. How might this tremendous diversity of potassium channels be generated? Partial answers have begun to emerge as molecular studies of potassium channel genes have become possible over the past few years.

Animals↗
PubMed2005

Effects of calcium channel blocker, mibefradil, and potassium channel opener, pinacidil, on the contractile response of mid-pregnant goat myometrium.

The present study was undertaken to investigate the in vitro influence of mibefradil, a calcium channel blocker, and pinacidil, a potassium channel opener, on pregnant goat myometrial spontaneous rhythmic contractility and contractions induced with the agonist, oxytocin. Longitudinal strips from the distal region of uterus, collected from goats at midgestation, were mounted in an organ bath for recording isometric contractions. Mibefradil (10(-8)-10(-4) M) or pinacidil (10(-10)-10(-4) M), added cumulatively to the bath at an increment of 1 log unit, caused concentration-dependent inhibition of the spontaneous rhythmic contractions of isolated uterine strips. The rhythmic contraction was, respectively, abolished at 100 and 10 microM concentrations of mibefradil and pinacidil. In a concentration-dependent manner, mibefradil (1 and 10 microM) antagonized the contractions elicited with oxytocin (10(-5)-10(-2) IU). Pretreatment of uterine strips with glibenclamide (10 microM), a selective KATP channel blocker, caused a rightward shift of the concentration-response curve of pinacidil with a concomitant decrease in its pD2 value. Pinacidil (0.3, 1 and 3 microM), in a concentration-related manner, antagonized the oxytocin (10(-5)-10(-2) IU)-induced contractile response. The inhibition of spontaneous rhythmic contractions and antagonism of oxytocin-induced contraction by mibefradil in the pregnant goat myometrium may be related to the antagonism of voltage-dependent Ca2+ channels, while by pinacidil suggests that KATP channel could be a therapeutic target for tocolysis.

Adenosine Triphosphate↗
PubMed2001

Formation of functional heterodimers between the TASK-1 and TASK-3 two-pore domain potassium channel subunits.

The potassium channels in the two-pore domain family are widely expressed and regulate the excitability of neurons and other excitable cells. These channels have been shown to function as dimers, but heteromerization between the various channel subunits has not yet been reported. Here we demonstrate that two members of the TASK subfamily of potassium channels, TASK-1 and TASK-3, can form functional heterodimers when expressed in Xenopus laevis oocytes. To recognize the two TASK channel types, we took advantage of the higher sensitivity of TASK-1 over TASK-3 to physiological pH changes and the discriminating sensitivity of TASK-3 to the cationic dye ruthenium red. These features were clearly observed when the channels were expressed individually. However, when TASK-1 and TASK-3 were expressed together, the resulting current showed intermediate pH sensitivity and ruthenium red insensitivity (characteristic of TASK-1), indicating the formation of TASK-1/TASK-3 heterodimers. Expression of a tandem construct in which TASK-3 and TASK-1 were linked together yielded currents with features very similar to those observed when coexpressing the two channels. The tandem construct also responded to AT(1a) angiotensin II receptor stimulation with an inhibition that was weaker than the inhibition of homodimeric TASK-1 and greater than that shown by TASK-3. Expression of epitope-tagged channels in mammalian cells showed their primary presence in the plasma membrane consistent with their function in this location. Heteromerization of two-pore domain potassium channels may provide a greater functional diversity and additional means by which they can be regulated in their native tissues.

Angiotensin II↗
PubMed1996

[K+] dependence of open-channel conductance in cloned inward rectifier potassium channels (IRK1, Kir2.1).

Potassium conduction through unblocked inwardly rectifying (IRK1, Kir2.1) potassium channels was measured in inside-out-patches from Xenopus oocytes, after removal of polyamine-induced strong inward rectification. Unblocked IRK1 channel current-voltage (I-V) relations show very mild inward rectification in symmetrical solutions, are linearized in nonsymmetrical solutions that bring the K+ reversal potential to extreme negative values, and follow Goldman-Hodgkin-Katz constant field equation at extreme positive E alpha. When intracellular K+ concentration (KIN) was varied, at constant extracellular K+ concentration (KOUT) the conductance at the reversal potential (GREV) followed closely the predictions of the Goldman-Hodgkin-Katz constant field equation at low concentrations and saturated sharply at concentrations of > 150 mM. Similarly, when KOUT was varied, at constant KIN, GREV saturated at concentrations of > 150 mM. A square-root dependence of conductance on KOUT is a well-known property of inward rectifier potassium channels and is a property of the open channel. A nonsymmetrical two-site three-barrier model can qualitatively explain both the I-V relations and the [K+] dependence of conductance of open IRK1 (Kir2.1) channels.

Animals↗
PubMed1989

Interactions between dendrotoxin, a blocker of voltage-dependent potassium channels, and charybdotoxin, a blocker of calcium-activated potassium channels, at binding sites on neuronal membranes.

Dendrotoxin I (DpI) from black mamba venom (Dendroaspis polylepis) has high affinity binding sites on rat brain synaptic membranes. Native DpI displaced [125I]-DpI binding with a Ki of 1 x 10(-10) M, and over 90% of specific binding was displaceable. Charybdotoxin isolated from the Israeli scorpion venom (Leiurus quinquestriatus hebraeus), also displaced [125I]-DpI binding, with a Ki of approximately 3 x 10(-9) M, although the displacement curve was shallower than with native DpI. Both toxins are thought to be high affinity blockers of specific K+ currents. Charybdotoxin selectively blocks some types of Ca2+-activated K+ channels, whereas dendrotoxins only block certain voltage-dependent K+ channels. The interaction between the two types of toxin at the DpI binding site is unexpected and may suggest the presence of related binding sites on different K+ channel proteins.

Animals↗
PubMed2004

Modeling P-loops domain of sodium channel: homology with potassium channels and interaction with ligands.

A large body of experimental data on Na+ channels is available, but the interpretation of these data in structural terms is difficult in the absence of a high-resolution structure. Essentially different electrophysiological and pharmacological properties of Na+ and K+ channels and poor identity of their sequences obstruct homology modeling of Na+ channels. In this work, we built the P-loops model of the Na+ channel, in which the pore helices are arranged exactly as in the MthK bacterial K+ channel. The conformation of the selectivity-filter region, which includes residues in positions -2 through +4 from the DEKA locus, was shaped around rigid molecules of saxitoxin and tetrodotoxin that are known to form multiple contacts with this region. Intensive Monte Carlo minimization that started from the MthK-like conformation produced practically identical saxitoxin- and tetrodotoxin-based models. The latter was tested to explain a wide range of experimental data that were not used at the model building stage. The docking of tetrodotoxin analogs unambiguously predicted their optimal orientation and the interaction energy that correlates with the experimental activity. The docking of mu-conotoxin produced a binding model consistent with experimentally known toxin-channel contacts. Monte Carlo-minimized energy profiles of tetramethylammonium pulled through the selectivity-filter region explain the paradoxical experimental data that this organic cation permeates via the DEAA but not the AAAA mutant of the DEKA locus. The model is also consistent with earlier proposed concepts on the Na+ channel selectivity as well as Ca2+ selectivity of the EEEE mutant of the DEKA locus. Thus, the model integrates available experimental data on the Na+ channel P-loops domain, and suggests that it is more similar to K+ channels than was believed before.

Amino Acid Sequence↗
PubMed2000

Analogue pattern matching in a dendritic spine model based on phosphorylation of potassium channels.

Modification of potassium channels by protein phosphorylation has been shown to play a role in learning and memory. If such memory storage machinery were part of dendritic spines, then a set of spines could act as an 'analogue pattern matching' device by learning a repeatedly presented pattern of synaptic activation. In this study, the plausibility of such analogue pattern matching is investigated in a detailed circuit model of a set of spines attached to a dendritic branch. Each spine head contains an AMPA synaptic channel in parallel with a calcium-dependent potassium channel whose sensitivity depends on its phosphorylation state. Repeated presentation of synaptic activity results in calcium activation of protein kinases and subsequent channel phosphorylation. Simulations demonstrate that signal strength is greatest when the synaptic input pattern is equal to the previously learned pattern, and smaller when components of the synaptic input pattern are either smaller or larger than corresponding components of the previously learned pattern. Therefore, our results indicate that dendritic spines may act as an analogue pattern matching device, and suggest that modulation of potassium channels by protein kinases may mediate neuronal pattern recognition.

Animals↗
PubMed1988

Single-channel analysis of four distinct classes of potassium channels in Drosophila muscle.

A number of mutations have been shown to affect potassium channels in Drosophila muscle. Single-channel analysis of the effects of mutations will prove a powerful approach for studying the molecular mechanisms of ion channel gating. As an initial step towards studying the effects of mutations at the single-channel level, we have characterized wild-type potassium channels in cultured embryonic myotubes using whole-cell, cell-attached, inside-out, and outside-out configurations of the patch-clamp technique. The myotubes differentiate in vitro from primary cultures of late-gastrula stage embryos of Drosophila. The whole-cell outward currents develop in a characteristic sequence. At 8 hr after plating a small delayed outward current is present. Between 10 and 12 hr after plating an A-type outward current develops, followed, between 13 and 16 hr, by a large increase in the delayed current. The A-type current is absent at all developmental stages in myotubes homozygous for the mutant ShKS133. At least 4 different types of potassium channels contribute to the whole-cell outward currents: a fast transient 14 pS A-type potassium channel (A1), a slowly inactivating 14 pS potassium channel (KD), a 40 pS potassium channel that does not inactivate during voltage pulses up to 2.4 sec in duration (KO), and a 90 pS potassium channel that is strongly activated by membrane stretch (KST). Channels indistinguishable from the KD and KST channels were also observed in patch-clamp studies on larval body wall muscle fibers. A1 channels were also present in intact dorsal longitudinal flight muscles. The A1 channel underlies the rapidly inactivating component of the whole-cell current. It inactivates with a similar time course and voltage dependence to the A-current and is similarly blocked by 5 mM 4-aminopyridine. The KD channel underlies a large fraction of the delayed component of the whole-cell current. Ensemble averages of single KD channels inactivate with the same time course as the delayed current. The KO channel represents a smaller fraction of the whole-cell delayed outward current. Its increase in open probability with voltage is due primarily to a voltage dependence of its closed times. The KST channel is voltage and calcium independent and would therefore only contribute to the leak whole-cell current.

Animals↗
PubMed1999

Stoichiometry of potassium channel opener action.

Potassium channel openers (KCOs; e.g., P1075, pinacidil) exert their effects on excitable cells by opening ATP-sensitive potassium channels. These channels are heteromultimers composed with a 4:4 stoichiometry of an inwardly rectifying K(+) channel subunit plus a regulatory subunit comprising the receptor sites for hypoglycemic sulfonylureas and KCOs (a sulfonylurea receptor). To elucidate stoichiometry of KCO action, we analyzed P1075 sensitivity of channels coassembled from sulfonylurea receptor isoforms with high or low P1075 affinity. Concentration activation curves for cDNA ratios of 1:1 or 1:10 resembled those for channel opening resulting from interaction with a single site, whereas models for activation requiring occupation of two, three, or four sites were incongruous. We conclude KCO-induced channel activation to be mediated by interaction with a single binding site per tetradimeric complex.

ATP-Binding Cassette Transporters↗
PubMed1999

Transmembrane structure of an inwardly rectifying potassium channel.

Inwardly rectifying potassium channels (K(ir)), comprising four subunits each with two transmembrane domains, M1 and M2, regulate many important physiological processes. We employed a yeast genetic screen to identify functional channels from libraries of K(ir) 2.1 containing mutagenized M1 or M2 domains. Patterns in the allowed sequences indicate that M1 and M2 are helices. Protein-lipid and protein-water interaction surfaces identified by the patterns were verified by sequence minimization experiments. Second-site suppressor analyses of helix packing indicate that the M2 pore-lining inner helices are surrounded by the M1 lipid-facing outer helices, arranged such that the M1 helices participate in subunit-subunit interactions. This arrangement is distinctly different from the structure of a bacterial potassium channel with the same topology and identifies helix-packing residues as hallmark sequences common to all K(ir) superfamily members.

Amino Acid Sequence↗
PubMed1996

Regions responsible for the assembly of inwardly rectifying potassium channels.

Inwardly rectifying potassium channels have an important role in determining the resting potential of the cell. They are tetrameric proteins with two transmembrane segments (M1 and M2), a pore-forming loop (H5), a cytoplasmic N-terminal, and longer C-terminal domain. We have used biochemical and electrophysiological methods to identify regions required for homotypic interactions and those responsible for the incompatibility between IRK1 and two other members of the same subfamily (IRK2 and IRK3) and two members from other subfamilies (ROMK1 and 6.1 uK(ATP)). The data indicate that, in contrast to the voltage-gated class of potassium channel, the proximal C-terminus and the transmembrane segment M2 determine homo-and heteromultimerization and that heteromultimerization between members of the same or different subfamilies is case specific.

Animals↗
PubMed1998

Voltage-dependent, open channel blockade of the cardiac sarcoplasmic reticulum potassium channel by 4-aminopyridine.

The nature of open state block was characterized in isolated canine cardiac sarcoplasmic reticulum (SR) potassium channel incorporated into planar lipid bilayers. 4-Aminopyridine (4-AP) blocked the open conductance state of the potassium channels in a voltage-dependent manner. Blockade was reversible, occurred from either the cis (cytoplasmic) or the trans (lumenal) side and was competitive with potassium ions. Reversal potential measurements indicated that this channel was impermeable to 4-AP. Measured effective electrical distances were roughly symmetrical and indicated penetration of 0.39 and 0.42 of the membrane electrical field from the cis and trans sides, respectively. Effective electrical distance was insensitive to potassium ion concentration in the range 50 to 200 mM and indicated that 4-AP was able to penetrate relatively deeply into the pore compared with blockade of sarcolemmal potassium channels. Potassium ion concentration and voltage dependence of 4-AP blockade were consistent with a two binding site blockade model, similar to the model used previously to describe calcium ion blockade of the SR potassium ion channel. Unlike calcium blockade, however, 4-AP blocked from either cis or trans in a similar manner, suggesting a distinct binding site for each of these two blockers. Open channel, voltage-dependent blockade of the SR potassium channel by 4-AP is in marked contrast to its action on sarcolemmal potassium channels and suggests that either 4-AP penetrates much farther into the potassium channel permeation pathway than was previously believed, or the SR potassium channel has a very different physical pore arrangement from that of sarcolemmal potassium channels.

4-Aminopyridine↗
PubMed2006

Relaxant responses to calcium channel antagonists and potassium channel opener in human saphenous vein.

1.-- As shown in a parallel study the magnitude of depolarization induced in human saphenous vein by raising external potassium ([K(+)](e)) falls markedly below the theoretical values predicted by the Goldman-Hodgkin-Katz equations. This anomaly prompted us to re-examine the relaxant actions of L-type (nifedipine) and T-type (mibefradil) Ca(2+) channel antagonists, and relaxant and electrophysiological effects of the K(+) channel opener, pinacidil, on saphenous veins contracted by the elevation of [K(+)](e). 2.-- Nifedipine produced concentration-dependent relaxations in tissues contracted at various high [K(+)](e). In tissues contracted with 20 mm [K(+)](e), the pIC(50) for nifedipine was significantly (8.20 +/- 0.05; n = 6; mean +/- SEM; P < 0.05) greater than in tissues contracted with > or =40 mm [K(+)](e). 3.-- Tissues contracted with 20 mm [K(+)](e) also relaxed in response to mibefradil (pIC(50) = 6.1 +/- 0.14) and pinacidil (pIC(50) = 6.45 +/- 0.08), the latter being almost completely reversed (93.4 +/- 9.9%) by addition of glibenclamide (10 microm). 4.-- The resting E(m) of smooth muscle cells of saphenous vein was -77.0 +/- 0.7 mV (n = 52), and 20 mm [K(+)](e) produced a modest but significant depolarization to -73.0 +/- 0.7 mV (n = 52). Incubation with pinacidil plus 20 mm [K(+)](e) resulted in a significant hyperpolarization of the E(m) to -82 +/- 0.6 mV (n = 52). 5.-- N(omega)-nitro-L-arginine methyl ester did not impede the relaxant responses of nifedipine, mibefradil or pinacidil. 6.-- In conclusion, the relaxant effects of nifedipine and pinacidil (i) occurred at an E(m) distinctly below the presumed threshold for the opening of the classic (Ca(V)1.3alpha(1)) L-type Ca(2+) channels, and (ii) did not depend on generation of nitric oxide.

Calcium Channel Blockers↗