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PubMed1997

Clustering of KV4.2 potassium channels in postsynaptic membrane of rat supraoptic neurons: an ultrastructural study.

Ion channels play a key role in determining both neuronal membrane excitability and specificity. Neuronal specificity is achieved by several mechanisms, including the properties of the afferent network neurons are involved in, and the expression of specific sets of ion channels at the cellular level. In addition, subcellular distribution of channels might contribute to neuronal specificity, as suggested by the growing number of recent studies. Among ion channels, potassium (K+) channels have been shown to play an essential contribution in repolarization and interspike duration. Recently, K+ channel subtypes examined by light microscopy were reported to display a differential subcellular distribution in central neurons. But the precise localization of the channels on pre- or post-synaptic membrane was only assessed in a few brain areas. Here we used confocal and immunoelectron microscopic approaches to determine the hypothalamic localization of Kv4.2 K+ channels, which encode an A-type current. We found that intense immunostaining was localized to the supraoptic nucleus where it frequently formed rings outlining the somata of magnocellular neurons. Electron microscopy further revealed that this immunostaining was essentially associated with the plasma membrane limitating the somata or the dendrites of these neurons, and that it was particularly concentrated at the site of synaptic contacts. This is the first report showing clusters of voltage-gated channels on postsynaptic membranes in central mammalian neurons. The specific localization of the Kv4.2 channel indicates that this channel may play a role in signal integration at the synapse.

Animals↗
PubMed1998

KQT2, a new putative potassium channel family produced by alternative splicing. Isolation, genomic structure, and alternative splicing of the putative potassium channels.

Potassium (K+) channels are critical for a variety of cell functions, including modulation of action potentials, determination of the testing membrane potential, and development of memory and learning. Eleven mouse cDNA clones homologous to the new human putative K+ channel (designated HNSPC, which we recently reported) were isolated from the brain cDNA libraries. All these proteins coded by the isolated cDNAs were identical from the N-terminal to the sixth transmembrane domain, but exhibited differences in the sequence and length of the C-terminal cytoplasmic region. Analyses of the mouse genomic DNAs showed that these clones originated from a single gene located on mouse chromosome 2H3-4, which proved that these clones were generated by alternative RNA splicing. Since all isoforms showed significant structural identity with KVLQT1 (64% identity in the transmembrane domains), which is known to associate with IsK, they were designated mKQT2.1-mKQT2.11. Northern blot analysis indicated that the mRNAs of the mKQT2 isoforms were exclusively expressed in the brain. In the mouse cerebellum region, the localized expression of these clones in the Purkinje cell layer and Golgi cells was shown by in situ hybridization analysis. These transcripts were also detected in the mouse embryonic developmental stage (11th, 15th and 17th day); and in particular, the mRNAs for shorter forms (mKQT2.9, mKQT2.10 or mKQT2.11) were abundantly found on the 11th day after gestation. Although these mKQT2 isoforms had the characteristic structure of voltage-gated K+ channels, functional expression of K+ currents were not detected in Xenopus oocytes.

Alternative Splicing↗
PubMed2003

The use of the potassium channel activator riluzole to test whether potassium channels mediate the capacity of isoflurane to produce immobility.

UNLABELLED: Inhaled anesthetics produce immobility during noxious stimulation, primarily by actions on the spinal cord. In this study, we examined whether activation of potassium channels of the KCNK subfamily alters volatile anesthetic potency. We measured the change in isoflurane minimum alveolar anesthetic concentration (MAC) during 4-h intrathecal or IV infusions of the nonspecific KCNK activator riluzole in 54 Sprague-Dawley rats. IV or intrathecal infusions of riluzole doses that did not result in permanent injury or death equally decreased isoflurane MAC. We conclude that although riluzole exhibited anesthetic effects, the similar dose response from IV or intrathecal infusion suggests systemic absorption and actions in the brain rather than the spinal cord. IMPLICATIONS: Riluzole, a drug that activates potassium channels and decreases glutamatergic neurotransmission, primarily acts on supraspinal sites to produce immobility in response to noxious stimuli. This finding does not support the hypothesis that potassium channels mediate the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation.

Anesthetics, Inhalation↗
PubMed1987

Cholinergic receptor-regulation of potassium channels and potassium transport in human submandibular acinar cells.

The cholinergic receptor-regulation of K+ transport was studied in human submandibular glands. Acetylcholine stimulation 10 mumol/L results in an increase in membrane permeability (86Rb+ efflux) for, and a net efflux of, K+ ions from the glandular tissue. In the post-stimulus period, there is a net re-uptake of K+ ions into the tissue. Patch-clamp electrophysiological techniques were employed to demonstrate the presence of a large conductance K+ selective ion channel in the basolateral membranes of isolated human submandibular acinar cells. The patch-clamp results indicate that this voltage- and calcium-activated K+ channel operates to regulate the K+ permeability in both the resting and acetylcholine-stimulated acinar cells. We discuss the role of the K+ channel, K+ efflux, and K+ re-uptake in relation to stimulus-secretion coupling.

Acetylcholine↗
PubMed1999

The effects of level of expression of a jellyfish Shaker potassium channel: a positive potassium feedback mechanism.

1. When jellyfish Shaker potassium channels (jShak2) are heterologously expressed in Xenopus oocytes at different levels they demonstrate density-dependent changes in electrical and kinetic properties of macroscopic currents. 2. The activation and inactivation properties of jShak2 channels depend on the extracellular potassium concentration. In this study we present experimental data which show that expression-dependent changes in kinetic and electrical properties of jShak2 macroscopic currents can be explained by the positive feedback effect of dynamic accumulation of K+ in the perimembranal space.

Animals↗
PubMed2002

Induction of nitric oxide and respiratory burst response in activated goldfish macrophages requires potassium channel activity.

Potassium channel activity is important for modulating mammalian macrophage antimicrobial functions. The involvement of potassium channels in mediation of immune cell function in lower vertebrates, such as teleost, has not been explored. Since relatively little is known about the types of potassium channels present in fish macrophages, pharmacological blockers with broad ranges of activity were tested: 4-aminopyridine (4-AP), quinine, and tetraethylammonium chloride (TEA). The potassium channel blockers inhibited reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI) production by goldfish macrophages activated with bacterial lipopolysaccharide (LPS) and/or macrophage activating factor (MAF)-containing supernatants. Quinine was the most potent inhibitor with an IC(50) of 50 microM, while the other blockers, 4-AP and TEA, had IC(50) of 1.2 and 0.6mM, respectively. A reversible depolarization of the goldfish macrophage plasma membrane potential (Vm) was observed following treatments with potassium channel blockers, and was related to transcriptional changes in the inducible nitric oxide synthase gene (iNOS). Down-regulation of antimicrobial activities and depolarization of the goldfish macrophage plasma membrane were not a consequence of reduced cell number or viability, suggesting that potassium channels are required for generation of appropriate goldfish macrophage antimicrobial functions.

4-Aminopyridine↗
PubMedDate not supplied

Structure and function of potassium channels in plants: some inferences about the molecular origin of inward rectification in KAT1 channels (Review).

Potassium channels in plants play a variety of important physiological roles including K(+) uptake into roots, stomatal and leaf movements, and release of K(+) into the xylem. This review summarizes current knowledge about a class of plant genes whose products are K(+) channel-forming proteins. Potassium channels of this class belong to a superfamily characterized by six membrane-spanning domains (S1-6), a positively charged S4 domain and a region between the S5 and S6 segments that forms the channel selectivity filter. These channels are voltage dependent, which means the membrane potential modifies the probability of opening (P(o)). However, despite these channels sharing the same topology as the outward-rectifying K(+) channels, which are activated by membrane depolarization, some plant K(+) channels such as KAT1/2 and KST1 open with hyperpolarizing voltages. In outward-rectifying K(+) channels, the change in P(o) is achieved through a voltage sensor formed by the S4 segment that detects the voltage transferring its energy to the gate that controls pore opening. This coupling is achieved by an outward displacement of the charges contained in S4. In KAT1, most of the results indicate that S4 is the voltage sensor. However, how the movement of S4 leads to opening remains unanswered. On the basis of recent data, we propose here that in plant-inward rectifiers an inward movement of S4 leads to channel opening and that the difference between it and outward-rectifying channels resides in the mechanism that couples gating charge displacement with pore opening.

Amino Acid Sequence↗
PubMed2002

Selective coupling of T-type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons.

Dopaminergic midbrain (DA) neurons display two principal activity patterns in vivo, single-spike and burst firing, the latter coding for reward-related events. We have shown recently that the small-conductance calcium-activated potassium channel SK3 controls pacemaker frequency and precision in DA neurons of the substantia nigra (SN), and previous studies have implicated SK channels in the transition to burst firing. To identify the upstream calcium sources for SK channel activation in DA SN neurons, we studied the sensitivity of SK channel-mediated afterhyperpolarization (AHP) currents to inhibitors of different types of voltage-gated calcium channels in perforated patch-clamp recordings. Cobalt-sensitive AHP currents were not affected by L-type and P/Q-type calcium channel inhibitors and were reduced slightly (26%) by the N-type channel inhibitor omega-conotoxin-GVIA. In contrast, AHP currents were blocked substantially (85-94%) by micromolar concentrations of nickel (IC50, 33.75 microm) and mibefradil (IC50, 4.83 microm), indistinguishable from the nickel and mibefradil sensitivities of T-type calcium currents (IC50 values, 33.86 and 4.59 microm, respectively). These results indicate that SK channels are activated selectively via T-type calcium channels in DA SN neurons. Consequently, SK currents displayed use-dependent inactivation with similar time constants when compared with those of T-type calcium currents and generated a transient rebound inhibition. Both SK and T-type channels were essential for the stability of spontaneous pacemaker activity, and, in some DA SN neurons, T-type channel inhibition was sufficient to induce intrinsic burst firing. The functional coupling of SK to T-type channels has important implications for the temporal integration of synaptic input and might help to understand how DA neurons switch between pacemaker and burst-firing modes in vivo.

Action Potentials↗
PubMed1999

TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium channel family.

Potassium channels are found in all mammalian cell types, and they perform many distinct functions in both excitable and non-excitable cells. These functions are subserved by several different families of potassium channels distinguishable by primary sequence features as well as by physiological characteristics. Of these families, the tandem pore domain potassium channels are a new and distinct class, primarily distinguished by the presence of two pore-forming domains within a single polypeptide chain. We have cloned a new member of this family, TWIK-2, from a human brain cDNA library. Primary sequence analysis of TWIK-2 shows that it is most closely related to TWIK-1, especially in the pore-forming domains. Northern blot analysis reveals the expression of TWIK-2 in all human tissues assayed except skeletal muscle. Human TWIK-2 expressed heterologously in Xenopus oocytes is a non-inactivating weak inward rectifier with channel properties similar to TWIK-1. Pharmacologically, TWIK-2 channels are distinct from TWIK-1 channels in their response to quinidine, quinine, and barium. TWIK-2 is inhibited by intracellular, but not extracellular, acidification. This new clone reveals the existence of a subfamily in the tandem pore domain potassium channel family with weak inward rectification properties.

Amino Acid Sequence↗
PubMed1998

Effects of ATP-sensitive potassium channel opener on potassium transport and alveolar fluid clearance in the resected human lung.

Since the effect of an ATP-sensitive potassium channel (KATP channel) opener on the function of alveolar epithelial cells is unknown, the effect of YM934, a newly synthesized KATP channel opener, on potassium influx into the alveolar spaces and alveolar fluid clearance was determined in the resected human lung. An isosmolar albumin solution with a low potassium concentration was instilled into the distal airspaces of resected human lungs. Alveolar fluid clearance was measured by the progressive increase in alveolar protein concentration. Net potassium transport was measured by the change in potassium concentration and alveolar fluid volume. YM934 (10(-4) M) increased net influx of potassium by 140% into the alveolar spaces and also increased alveolar fluid clearance by 60% in the experiments with a potassium concentration of 0.3 mEq/1. Glibenclamide (10(-4) M), a KATP channel blocker, inhibited the YM934-increased influx of potassium transport and the increase in alveolar fluid clearance. Also amiloride (10(-5) M), an inhibitors of apical sodium uptake, blocked the YM934 stimulated increase in net alveolar fluid clearance. These results indicate that a KATP channel opener can effect potassium transport and net vectorial fluid movement across the human alveolar epithelium.

Adenosine Triphosphate↗
PubMed1997

Kainic acid-induced generalized seizures alter the regional hippocampal expression of the rat Kv4.2 potassium channel gene.

Potassium channels play a key role in the regulation of membrane excitability. We investigated the gene expression response of the Kv4.2 subtype of potassium channel, in the rat hippocampus, to a brief (5 min) episode of kainic acid-induced seizures. Our results demonstrate that Kv4.2 expression is reduced in the granule cell layer of the dentate gyrus at 3 h post-seizure, while no significant changes in expression are observed in other hippocampal subfields. At 6 h post-challenge, expression in both dentate hilar cells and granule cells is reduced, while no other significant changes are observed. At 24 h post-challenge, expression levels for Kv4.2 in the dentate granule cells have rebounded to levels greater than control, while expression levels are significantly reduced in the CA3 and CA4 subfields. No significant changes in Kv4.2 expression are observed in kainic acid-administered animals that fail to seize, indicating that the changes in gene expression result from seizure activity and not from the direct actions of the administered kainic acid. These results demonstrate that brief kainic acid-induced epileptiform activity promotes alterations in the expression levels for the Kv4.2 subtype of potassium channel gene.

Animals↗
PubMed2004

KCNE1 binds to the KCNQ1 pore to regulate potassium channel activity.

Potassium channels control the resting membrane potential and excitability of biological tissues. Many voltage-gated potassium channels are controlled through interactions with accessory subunits of the KCNE family through mechanisms still not known. Gating of mammalian channel KCNQ1 is dramatically regulated by KCNE subunits. We have found that multiple segments of the channel pore structure bind to the accessory protein KCNE1. The sites that confer KCNE1 binding are necessary for the functional interaction, and all sites must be present in the channel together for proper regulation by the accessory subunit. Specific gating control is localized to a single site of interaction between the ion channel and accessory subunit. Thus, direct physical interaction with the ion channel pore is the basis of KCNE1 regulation of K+ channels.

Animals↗
PubMed2000

Genomic organization and chromosomal localization of the murine 2 P domain potassium channel gene Kcnk8: conservation of gene structure in 2 P domain potassium channels.

A 2 P domain potassium channel expressed in eye, lung, and stomach, Kcnk8, has recently been identified. To initiate further biochemical and genetic studies of this channel, we assembled the murine Kcnk8 cDNA sequence, characterized the genomic structure of the Kcnk8 gene, determined its chromosomal localization, and analyzed its activity in a Xenopus laevis oocyte expression system. The composite cDNA has an open reading frame of 1029 bp and encodes a protein of 343 amino acids with a predicted molecular mass of 36 kDa. Structure analyses predict 2 P domains and four potential transmembrane helices with a potential single EF-hand motif and four potential SH3-binding motifs in the COOH-terminus. Cloning of the Kcnk8 chromosomal gene revealed that it is composed of three exons distributed over 4 kb of genomic DNA. Genome database searching revealed that one of the intron/exon boundaries identified in Kcnk8 is present in other mammalian 2 P domain potassium channels genes and many C. elegans 2P domain potassium channel genes, revealing evolutionary conservation of gene structure. Using fluorescence in situ hybridization, the murine Kcnk8 gene was mapped to chromosome 19, 2B, the locus of the murine dancer phenotype, and syntenic to 11q11-11q13, the location of the human homologue. No significant currents were generated in a Xenopus laevis oocyte expression system using the composite Kcnk8 cDNA sequence, suggesting, like many potassium channels, additional channel subunits, modulator substances, or cellular chaperones are required for channel function.

Amino Acid Sequence↗
PubMed1995

The effect of AL0671, a novel potassium channel opener, on potassium current in rat aortic smooth muscle cells.

1. We evaluated the mechanism of activation by AL0671, a novel potassium channel opener, of potassium current in rat aortic smooth muscle cells. 2. Under conditions of whole cell recording, AL0671 (1-1000 microM) markedly increased potassium current with a Hill coefficient of 2 and dissociation constant of 1.5 x 10(-4) M. This activation was completely inhibited by intracellular ATP. 3. Under inside-out patch conditions, the ATP-sensitive K+ channels (KATP) treated with AL0671 (100 microM) showed prolongation of the slower open time component and shortening of the slower closed time component without modification of channel conductance.

Animals↗
PubMed2003

KCNE4 is an inhibitory subunit to Kv1.1 and Kv1.3 potassium channels.

Kv1 potassium channels are widely distributed in mammalian tissues and are involved in a variety of functions from controlling the firing rate of neurons to maturation of T-lymphocytes. Here we show that the newly described KCNE4 beta-subunit has a drastic inhibitory effect on currents generated by Kv1.1 and Kv1.3 potassium channels. The inhibition is found on channels expressed heterologously in both Xenopus oocytes and mammalian HEK293 cells. mKCNE4 does not inhibit Kv1.2, Kv1.4, Kv1.5, or Kv4.3 homomeric complexes, but it does significantly reduce current through Kv1.1/Kv1.2 and Kv1.2/Kv1.3 heteromeric complexes. Confocal microscopy and Western blotting reveal that Kv1.1 is present at the cell surface together with KCNE4. Real-time RT-PCR shows a relatively high presence of mKCNE4 mRNA in several organs, including uterus, kidney, lung, intestine, and in embryo, whereas a much lower mRNA level is detected in the heart and in five different parts of the brain. Having the broad distribution of Kv1 channels in mind, the demonstrated inhibitory property of KCNE4-subunits could locally and/or transiently have a dramatic influence on cellular excitability and on setting resting membrane potentials.

Adsorption↗
PubMed1999

Voltage-gated, margatoxin-sensitive potassium channels, but not calcium-gated, iberiotoxin-sensitive potassium channels modulate acetylcholine release in rat striatal slices.

We evaluated the effects of iberiotoxin, an inhibitor of Slo-type Ca2+-activated potassium channels and two inhibitors of Shaker-type voltage-gated potassium channels margatoxin and dendrotoxin on acetylcholine outflow in rat striatal slices. An in vitro perfusion with 100 nM margatoxin or dendrotoxin induced a concentration-dependent and tetrodotoxin-sensitive enhancement in spontaneous acetylcholine release. In contrast, a perfusion with iberiotoxin did neither modulate basal, nor electrically- or N-methyl-d-aspartate-induced transmitter release. Therefore, Slo-type Ca2+-activated K+-channels do not seem to contribute significantly to cholinergic neurotransmission within rat striatal slices. As the Kv1.2 subtype represents the only common high affinity binding site of margatoxin and dendrotoxin and the effects of these toxins are not additive, this subtype is suggested to be the channel utilized by margatoxin and dendrotoxin to release acetylcholine in this model.

Acetylcholine↗
PubMedDate not supplied

[Possibilities of the pharmacologic regulation of potassium channel function].

Potassium channels of excitable membranes are a heterogeneous group of channels among which one can distinguish potential-dependent, Ca2+-dependent, receptor-dependent and others. The substances contributing to the activation of these channels decrease excitability of membranes and the substances suppressing the activity of potassium channels increase it. A number of agents (narcotic analgetics, ligands of sigma-opiate receptors, GABA -mimetics, M-cholinergic agent) might modulate the activity of potassium channels indirectly through the corresponding receptors. Also, some drugs used in medical practice exert the immediate effect on these channels. Among them there are myotropic hypotensive drugs diazoxide, pinacidyl, BRL 34915 and minoxydyl, antidiabetic agents -- the derivatives of sulfon urea (butamide). The transfer of potassium ions through membranes is probably one of the fundamental mechanisms of the action of pharmacological agents.

Animals↗
PubMed1993

Intracellular protons control the affinity of skeletal muscle ATP-sensitive K+ channels for potassium-channel-openers.

Levcromakalim, a potential antihypertensive agent, is known to activate potassium channels dependent on intracellular ATP (K-ATP channels). In inside-out patches excised from frog skeletal muscle, levcromakalim or a related compound, SR 47063, caused a strong and persistent activation of K-ATP channels at a cytoplasmic pH of 7.1. However, at pH 6, these activators could no longer affect the K-ATP currents. Conversely, in the continuous presence of activator, lowering pH from 7.1 to 6 returned channel activity to its level in pH 6 alone. After wash-out of the activator, recovery from activation took minutes at pH 7.1 but only seconds at pH 6, thus ruling out an effect of protons on the activators in solution. These experiments suggest that K-channel-activators are unable to bind to their receptor when it is protonated, and more generally, they provide evidence at the microscopic level for proton-induced allosteric modulation of drug-receptor interaction.

Adenosine Triphosphate↗