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PubMed1996

State-dependent modulation of mSlo, a cloned calcium-dependent potassium channel.

The mouse slopoke calcium-dependent potassium channel (mSlo) has been expressed heterologously in COS cells, and incorporated from COS cell membranes into artificial phospholipid bilayers. Under control conditions, the channel is not modulated by ATP. However, when mSlo is treated first with the calcium-dependent potassium channel opener NS004, which itself increases the open probability of the channel, subsequent addition of ATP causes a large further increase in channel open probability. An increase in channel activity is not by itself sufficient to confer sensitivity to ATP, because ATP does not modulate channels whose open probability has been increased by elevated calcium or depolarized voltage. The ATP analog AMP-PNP has only minimal effects on channel activity after treatment with NS004, suggesting that hydrolysis of the ATP is required for its action on mSlo. A peptide inhibitor of the calcium/calmodulin-dependent protein kinase II (CaMKII) blocks the modulation of mSlo by ATP, whereas peptide inhibitors of other serine/threonine protein kinases are without effect. The results are consistent with a state-dependent modulation of mSlo by ATP, possibly via phosphorylation.

Adenosine Triphosphate↗
PubMed2001

Angular methoxy-substituted furo- and pyranoquinolinones as blockers of the voltage-gated potassium channel Kv1.3.

The voltage-gated potassium channel Kv1.3 constitutes an attractive target for immunosuppression because of its role in T-lymphocyte activation and its functionally restricted expression to lymphocytes. Blockade of Kv1.3 channels by margatoxin has previously been shown to prevent T-cell activation and attenuate immune responses in vivo. In the present study, several furo- and pyranoquinoline derivatives were synthesized and screened for their blocking activities of Kv1.3 channels, stably expressed in mice-fibroblasts L929. In addition the activities of the compounds on Kv currents of the neuroblastoma cell line N1E-115 were determined. The most potent compounds, the angular furoquinolinone 8-methoxy-2-(1'-methylethyl)-5-methyl-4,5-dihydrofuro[3,2-c]quinolin-4-one (8c) and the angular pyranoquinolinone 9-methoxy-2,2,6-trimethyl-2,6-dihydro-5H-pyrano[3,2-c]quinolin-5-one (9a), inhibited Kv1.3 channels with half-blocking concentrations of 5 and 10 microM, respectively, and displayed 8-fold (8c) and 2-fold (9a) selectivity over Kv currents of N1E-115 cells. Thus, compounds 8c and 9a might function as a template for the development of novel immunosuppressants.

Animals↗
PubMed1985

Differential blockage of two types of potassium channels in the crab giant axon.

Measurements were made of the kinetic and steady-state characteristics of the potassium conductance in the giant axon of the crabs Carcinus maenas and Cancer pagirus. The conductance increase during depolarizing voltage-clamp pulses was analyzed assuming that two separate types of potassium channels exist in these axons (M.E. Quinta-Ferreira, E. Rojas and N. Arispe, J. Membrane Biol. 66:171-181, 1982). It is shown here that, with small concentrations of conventional K+-channel blockers, it is possible to differentially inhibit these channels. The potassium channels with activation and fast inactivation gating (m3h, Hodgkin-Huxley kinetics) were blocked by external application of 4 amino-pyridine (4-AP). The potassium channels with standard gating (n4, Hodgkin-Huxley kinetics) were preferentially inhibited by externally applied tetraethylammonium (TEA). The differential blockage of the two types of potassium conductance changes suggests that they represent two different populations of potassium channels. It is further shown here that blocking the early transient conductance increase leads to the inhibition of the repetitive electrical activity induced by constant depolarizing current injection in fibers from Cardisoma guanhumi.

4-Aminopyridine↗
PubMed1994

ATP-sensitive potassium channels: an overview.

ATP-sensitive potassium channels are found in a number of different tissues where they undertake distinct physiologic functions. In endocrine cells they regulate the secretion of hormones such as insulin, prolactin, and growth hormone. They influence the excitability of cardiac, skeletal, and vascular smooth muscle. They are of particular importance during ischemia in both the heart and the brain, where they intervene to reduce or delay cell death. Both electrophysiologic and pharmacologic evidence points toward ATP-sensitive potassium channels making up a class of ion channels with tissue-specific as well as functional differences. There is therefore considerable scope for the development of specific products to either enhance or inhibit the action of these ion channels under different pathologic conditions.

Adenosine Triphosphate↗
PubMed2001

Designed peptide analogues of the potassium channel blocker ShK toxin.

ShK toxin, a potassium channel blocker from the sea anemone Stichodactyla helianthus, is a 35-residue polypeptide cross-linked by 3 disulfide bridges. In an effort to generate truncated peptidic analogues of this potent channel blocker, we have evaluated three analogues, one in which the native sequence was truncated and then stabilized by the introduction of additional covalent links (a non-native disulfide and two lactam bridges), and two in which non-native structural scaffolds stabilized by disulfide and/or lactam bridges were modified to include key amino acid residues from the native toxin. The effect of introducing a lactam bridge in the first helix of ShK toxin (to create cyclo14/18[Lys14,Asp18]ShK) was also examined to confirm that this modification was compatible with activity. All four analogues were tested in vitro for their ability to block Kv1.3 potassium channels in Xenopus oocytes, and their solution structures were determined using 1H NMR spectroscopy. The lactam bridge in full-length ShK is well tolerated, with only a 5-fold reduction in binding to Kv1.3. The truncated and stabilized analogue was inactive, apparently due to a combination of slight deviations from the native structure and alterations to side chains required for binding. One of the peptide scaffolds was also inactive because it failed to adopt the required structure, but the other had a K(d) of 92 microM. This active peptide incorporated mimics of Lys22 and Tyr23, which are essential for activity in ShK, and an Arg residue that could mimic Arg11 or Arg24 in the native toxin. Modification of this peptide should produce a more potent, low molecular weight peptidic analogue which will be useful not only for further in vitro and in vivo studies of the effect of blocking Kv1.3, but also for mapping the interactions with the pore and vestibule of this K(+) channel that are required for potent blockade.

Amino Acid Sequence↗
PubMed2002

Molecular diversity of vascular potassium channel isoforms.

1. One essential role for potassium channels in vascular smooth muscle is to buffer cell excitation and counteract vasoconstrictive influences. Several molecular mechanisms regulate potassium channel function. The interaction of these mechanisms may be one method for fine-tuning potassium channel activity in response to various physiological and pathological challenges. 2. The most prevalent K+ channels in vascular smooth muscle are large-conductance calcium- and voltage-sensitive channels (maxi-K channels) and voltage-gated channels (Kv channels). Both channel types are complex molecular structures consisting of a pore-forming alpha-subunit and an ancillary beta-subunit. The maxi-K and Kv channel alpha-subunits assemble as tetramers and have S4 transmembrane domains that represent the putative voltage sensor. While most vascular smooth muscle cells identified to date contain both maxi-K and Kv channels, the expression of individual alpha-subunit isoforms and beta-subunit association occurs in a tissue-specific manner, thereby providing functional specificity. 3. The maxi-K channel alpha-subunit derives its molecular diversity by alternative splicing of a single-gene transcript to yield multiple isoforms that differ in their sensitivity to intracellular Ca2+ and voltage, cell surface expression and post- translational modification. The ability of this channel to assemble as a homo- or heterotetramer allows for fine-tuning control to intracellular regulators. Another level of diversity for this channel is in its association with accessory beta-subunits. Multiple beta-subunits have been identified that can arise either from separate genes or alternative splicing of a beta-subunit gene. The maxi-K channel beta-subunits modulate the channel's Ca2+ and voltage sensitivity and kinetic and pharmacological properties. 4. The Kv channel alpha-subunit derives its diverse nature by the expression of several genes. Similar to the maxi-K channel, this channel has been shown to assemble as a homo- and heterotetramer, which can significantly change the Kv current phenotype in a given cell type. Association with a number of the ancillary beta-subunits affects Kv channel function in several ways. Beta-subunits can induce inactivating properties and act as chaperones, thereby regulating channel cell-surface expression and current kinetics.

Animals↗
PubMed1995

Calcium-activated potassium channels are involved in the response of mouse Leydig cells to human chorionic gonadotropin.

The patch-clamp technique was used to investigate the involvement of ion channels in the response of Leydig cells to gonadotropic hormones (viz. hCG). Recordings in the cell-attached configuration (pipette containing 140 mM KCl) showed unitary events with conductance of 187.9 +/- 5.2 pS (N = 24 patches) in about 70% of the cells. These channels were potassium selective and the open channel probability (Po) was always about 1% for displacement of potential from the resting value in the range of -20 to +60 mV. Treatment of the cells with hCG (2 ng/ml) led to a large increase in the frequency of openings, concomitant with a reduction in the mean closed time and there was essentially no effect on the mean open time of the channel. Dibutyryl cAMP (100 microM) produced an effect similar to that of hCG and both required external calcium for their action. No direct effect of either dibutyryl cAMP or hCG were observed in inside-out patches. Reversal potential measurements on excised inside-out patches demonstrated that the channels were highly potassium selective with unitary conductance of about 206.8 +/- 6.36 pS (mean +/- SEM of 6 measurements), and an estimated permeability of 3.6 x 10(-13) +/- 0.2 x 10(-13) cm3/s (mean +/- SEM for 6 measurements), in symmetrical 140 mM KCl. The activity of the channel in excised patches was very sensitive to the free-calcium concentration on the intracellular surface of the channel. Po evaluated at +60 mV increased from 3% at 10 nM to 47% at 100 nM free calcium. The Hill coefficient under these conditions was 1.1. These results demonstrate that Leydig cells have a Ca2(+)-activated K+ channel of large unitary conductance, which can be activated upon the binding of hCG to receptors in the cell membrane.

Animals↗
PubMed1995

Pharmacology of the potassium channel openers.

The potassium-channel openers comprise a large number of molecules that can be classified into three basic groups: (1) agents like levcromakalim that open a small-conductance (10-30 pS) glibenclamide-sensitive K+ channel currently known as the ATP-sensitive K+ channel, KATP; (2) hybrid molecules, such as nicorandil, that open KATP channels and that also activate the enzyme-soluble guanylate cyclase; (3) molecules like dehydrosaponin 1 that open the large-conductance (100-150 pS) calcium-dependent K+ channel, BKCa. K(+)-channel openers in groups 1 and 2 are most potent on smooth muscle, but KATP channels in cardiac muscle, neurones and the pancreatic beta cell are also affected. In vivo, moderate to high doses produce a fall in diastolic pressure with reflex tachycardia; low doses may exert selective dilator effects on specific vascular beds with little effect on systemic pressure. In vitro, all smooth muscles are relaxed with loss of spontaneous electric and mechanical activity; hyperpolarization to the region of EK is often observed. These effects can be antagonized by glibenclamide and also by imidazolines and guanidines, such as phentolamine, guanethidine, and antazoline, agents that also inhibit the smooth muscle delayed rectifier channel, KV. The mode and site of action of the group 1 and 2 K(+)-channel openers is the subject of intense study. Irrespective of their specific mode of action, the K(+)-channel openers, especially the hybrid molecules such as nicorandil, constitute a novel and promising approach to the treatment of cardiovascular disease.

Animals↗
PubMed1998

Potassium diet as a determinant for the renal response to systemic potassium channel modulation in anesthetized rats.

The role of potassium intake in the response of kidney function and plasma renin activity (PRA) to systemic application of U37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydro chloride), a putative blocker of ATP-sensitive potassium channels (K(ATP)), and P1075 (N-cyano-N'-(1,1-dimethylpropyl)-N"-pyridylguanidine), an opener of K(ATP) channels, was studied in the anesthetized rat. It was found that under normal potassium diet (0.7% K), U37883A (15 mg/kg, i.v.) increased urinary flow rate (UV) and sodium excretion (UNaV), decreased urinary potassium excretion (UKV), and significantly diminished heart rate (HR) without affecting mean arterial blood pressure (MAP) or glomerular filtration rate (GFR). P1075 (10 microg/kg, i.v.) lowered UV, UNaV and UKV, at least in part due to the fall in MAP and GFR. PRA was diminished by U37883A and increased by P1075. Variation in potassium diet (0.04 or 2% K) left the response in MAP, HR or GFR to both potassium channel modulators essentially unchanged. The reduction in renal excretion rates to P1075 also appeared unaffected, further supporting a predominant role of the change in MAP and GFR in this response. Variation in potassium diet, however, elicited the following alterations: (1) under both low and high potassium diet U37883A did no longer cause a significant natriuresis; (2) U37883A elicited a significant kaliuresis under high potassium diet, whereas potassium excretion remained essentially unchanged on very low levels under low potassium diet; (3) the increase in PRA to P1075 was blunted under low potassium diet. Additional experiments provided evidence that P1075 releases renin from freshly isolated juxtaglomerular cells of rats on normal but not on low potassium diet. In summary, systemic potassium channel modulation employing U37883A or P1075, respectively, exerts distinct effects on blood pressure and heart rate independent of potassium diet. In contrast, potassium diet appears to be a determinant for the concomitant responses in plasma renin activity and renal sodium and potassium excretion.

Adamantane↗
PubMed2001

Identification of a trafficking determinant localized to the Kv1 potassium channel pore.

The repertoire of Kv1 potassium channels expressed in presynaptic terminals of mammalian central neurons is shaped by intrinsic trafficking signals that determine surface-expression efficiencies of homomeric and heteromeric Kv1 channel complexes. Here, we show that a determinant controlling surface expression of Kv1 channels is localized to the highly conserved pore region. Point-mutation analysis revealed two residues as critical for channel trafficking, one in the extracellular "turret" domain and one in the region distal to the selectivity filter. Interestingly, these same residues also form the binding sites for polypeptide neurotoxins. Our findings demonstrate a previously uncharacterized function for the channel-pore domain as a regulator of channel trafficking.

Amino Acid Sequence↗
PubMed1986

Potassium ion accumulation slows the closing rate of potassium channels in squid axons.

Potassium ion accumulation in the periaxonal space between squid axonal membrane and the Schwann cell surrounding the axon slows the rate of potassium channel closing to a degree that is consistent with the effect on channel closing of an equivalent change in the bulk external potassium concentration. The alteration of channel gating is independent of membrane potential, V, for V less than or equal to -60 mV, which suggests that the effect is mediated at a site on the outer surface of the membrane, rather than a site within the channel.

Animals↗
PubMed1997

Alternative splicing in the pore-forming region of shaker potassium channels.

We have cloned cDNAs for the shaker potassium channel gene from the spiny lobster Panulirus interruptus. As previously found in Drosophila, there is alternative splicing at the 5' and 3' ends of the coding region. However, in Panulirus shaker, alternative splicing also occurs within the pore-forming region of the protein. Three different splice variants were found within the P region, two of which bestow unique electrophysiological characteristics to channel function. Pore I and pore II variants differ in voltage dependence for activation, kinetics of inactivation, current rectification, and drug resistance. The pore 0 variant lacks a P region exon and does not produce a functional channel. This is the first example of alternative splicing within the pore-forming region of a voltage-dependent ion channel. We used a recently identified potassium channel blocker, kappa-conotoxin PVIIA, to study the physiological role of the two pore forms. The toxin selectively blocked one pore form, whereas the other form, heteromers between the two pore forms, and Panulirus shal were not blocked. When it was tested in the Panulirus stomatogastric ganglion, the toxin produced no effects on transient K+ currents or synaptic transmission between neurons.

Amino Acid Sequence↗
PubMed1990

Evidence for the formation of heteromultimeric potassium channels in Xenopus oocytes.

Potassium channels show a wide range of functional diversity. Nerve cells typically express a number of K+ channels that differ in their kinetics, single-channel conductance, pharmacology, and sensitivity to voltage and second messengers. The cloning of the Shaker gene in Drosophila, and of related genes, has revealed that the encoded K+ channel polypeptides resemble one of the four internally homologous domains of the alpha-subunits of Na+ channels and Ca2+ channels, indicating that K+ channels may form by the co-assembly of several polypeptides. In this report we provide evidence that the Shaker A-type K+ channels expressed in Xenopus oocytes contain several Shaker polypeptides, that heteromultimeric channels may form through assembly of different channel polypeptides, that the kinetics or pharmacology of some heteromultimeric channels differ from those of homomultimeric channels, and that channel polypeptides from the fruit fly can co-assemble with homologous polypeptides from the rat. We suggest that heteromultimer formation may increase K+ channel diversity beyond even the level expected from the large number of K+ channel genes and alternative splicing products.

Animals↗
PubMed2002

Potassium channels and vascular proliferation.

Potassium channels are currently the focus of much attention because of their recently discovered role in the regulation of vascular smooth muscle growth. Dramatic alterations in the expression and activity of K+ channels causing marked changes in the cell's electrical properties accompany enhanced growth of smooth muscle cells (SMCs). These findings indicate that alterations in K+ channel function are important for SMC proliferation. However, the mechanisms by which changes in K+ channel activity influence cellular growth pathways are poorly understood. The emergent electrical properties caused by modulation of K+ channels are associated with marked differences in the spatial and temporal organization of Ca2+ signaling. Thus, changes in K+ channel function may represent a universal mechanism by which Ca2+ signals are targeted towards activation of gene expression and cell growth. As enhanced growth of smooth muscle underlies many cardiovascular diseases and clinical pathologies, the identification of an important role for K+ channels in SMC proliferation indicates a new source of therapeutic targets to regulate proliferative vascular disorders.

Animals↗
PubMed1990

Molecular studies of voltage-gated potassium channels.

The cloning and characterization of the voltage-activated Shaker potassium channel gene in Drosophila have led to the identification of structural elements involved in potassium channel gating. As found for the voltage-activated sodium channel, the S4 segment, located in the conserved core of the protein, plays a central role in voltage-dependent activation. Potassium channels appear to be formed by the assembly of several polypeptides into multisubunit channels. This is directly analogous to the proposed folding of the four internally homologous pseudosubunits of sodium and calcium channels. The amino- and carboxy-terminal regions of Shaker channels are specialized for, and appear to interact in, inactivation gating. This interaction probably includes interaction between subunits, as may be said for the role in inactivation gating of the junction between the carboxyl terminus of the third domain and amino terminus of the fourth domain of sodium channel (Vassilev et al. 1988). The capacity for coassembly in potassium channels extends not only to the alternatively spliced products of the same gene, but also to the products of different genes. Heteromultimeric channels that are formed in this way have kinetic and pharmacological properties that differ from homomultimers of their constituents and, as such, broaden the functional diversity of channels that can be produced by any given number of compatible potassium channel genes.

Animals↗
PubMed1991

[Potassium channel activators. Perspectives in the treatment of arterial hypertension].

Potassium channel activators (PCAs) open the membrane potassium channels, thus increasing the cell potassium efflux. This results in hyperpolarization of the cell membrane, the main result of which is a reduction of the penetration of calcium into cells. The resulting decrease of intracellular Ca++ produces relaxation of the smooth muscle fibres, notably in blood vessels. In animals, PCAs reduce total peripheral resistance and lower blood pressure. These vasodilator and hypotensive effects are accompanied by reflex tachycardia and stimulation of the renin-angiotensin system and they are antagonized by glibenclamide, an antagonist of ATP-dependent potassium channels. Very recent experimental data have shown that in the ischaemic myocardium PCAs tend to improve the balance between oxygen supply and demand and to exert a cardioprotective effect. Up to now, the only use of PCAs has been in arterial hypertension, and the only drugs used are pinacidil, minoxidil and diazoxide. Unfortunately, the PCAs that are available at present are rather poorly tolerated, which limits their development in this particular field. However, their combination with beta-blockers and/or diuretics reduces the incidence of their side-effects and improves their effectiveness. A synergistic effect between PCAs and angiotensin-converting enzyme inhibitors is probable.

Antihypertensive Agents↗
PubMed1993

Antinociceptive activity of intrathecally administered potassium channel openers and opioid agonists: a common mechanism of action?

The potassium channel openers could share a common mechanism of action with the opiates in the production of antinociception because both classes of drugs have been shown to enhance potassium efflux. The i.t. administration of the potassium channel openers diazoxide, minoxidil, and lemakalim (BRL38227) produced antinociception as measured in the tail-flick test. The ED50's were 122, 184 and 35 micrograms/mouse, respectively. Minoxidil and lemakalim (BRL 38227) were full agonists, whereas diazoxide was a partial agonist. Diazoxide-induced antinociception was blocked by the potassium channel blockers glyburide, apamin and charybdotoxin. Minoxidil- and lemakalim (i.t.)-induced antinociception was blocked totally by only glyburide. The antinociception produced by the potassium channel openers (i.t.) was blocked differentially by opiate antagonists (i.t.). The antinociceptive effects of diazoxide were blocked by nor binaltorphimine, ICI 174,864 and naloxone. Minoxidil- and lemakalim-induced antinociception was blocked by naloxone and ICI 174,864, but not by nor-binaltorphimine. Naloxone (s.c.) shifted the dose-effect curve for minoxidil to the right in a parallel manner. Morphine-induced antinociception was partially blocked by glyburide and apamin, whereas that produced by DPDPE was blocked totally by apamin. U50, 488H-induced antinociception was blocked partially by apamin. The potassium channel openers (i.t.) were not cross tolerant to morphine when measured in the tail-flick test. Apamin and glyburide precipitated "withdrawal-like" symptoms in morphine-tolerant mice. The interaction of potassium channel openers and opioids probably does not represent a direct interaction of these two classes of drugs at a similar receptor, but rather may occur via an interaction with a common second messenger system such as calcium.

Analgesics↗
PubMed2006

Voltage-gated potassium channels: regulation by accessory subunits.

Voltage-gated potassium channels regulate cell membrane potential and excitability in neurons and other cell types. A precise control of neuronal action potential patterns underlies the basic functioning of the central and peripheral nervous system. This control relies on the adaptability of potassium channel activities. The functional diversity of potassium currents, however, far exceeds the considerable molecular diversity of this class of genes. Potassium current diversity contributes to the specificity of neuronal firing patterns and may be achieved by regulated transcription, RNA splicing, and posttranslational modifications. Another mechanism for regulation of potassium channel activity is through association with interacting proteins and accessory subunits. Here the authors highlight recent work that addresses this growing area of exploration and discuss areas of future investigation.

Action Potentials↗