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PubMed1990

Quinidine blocks adenosine 5'-triphosphate-sensitive potassium channels in heart.

The ATP-sensitive potassium channel current (IK-ATP) was studied in excised inside-out patches from rat ventricular cells at 20-23 degrees C. The bath solution contained 140 mM KF, and the pipette solution contained 140 mM KCl and 1.2 mM MgCl2. ATP (0.5 mM) in the bath inhibited IK-ATP. In the absence of ATP, 10 microM quinidine decreased open probability 67 +/- 1% (n = 6) at -50 mV and 28 +/- 12% at -130 mV (n = 5) without affecting single channel conductance (48-52 pS). The block increased with 25 and 50 microM quinidine and could be reversed on washing quinidine for several minutes. Interburst (closed) intervals were increased by quinidine, whereas open and closed time distributions within bursts were not changed. We conclude that quinidine blocks IK-ATP in a "slow" and voltage-dependent manner in clinically relevant concentrations. Because of the postulated role for IK-ATP in cardiac ischemia, quinidine block of this channel may play a role in ischemic arrhythmias.

Adenosine Triphosphate↗
PubMed1997

Characterization of apical potassium channels induced in rat distal colon during potassium adaptation.

1. Chronic dietary K+ loading stimulates an active K+ secretory process in rat distal colon, which involves an increase in the macroscopic apical K+ conductance of surface epithelial cells. In the present study, the abundance and characteristics of K+ channels constituting this enhanced apical K+ conductance were evaluated using patch clamp recording techniques. 2. In isolated non-polarized surface cells, K+ channels were seen in 9 of 90 (10%) cell-attached patches in cells from control animals, and in 247 of 437 (57%) cell-attached patches in cells from K(+)-loaded animals, with a significant (P < 0.001) shift in distribution density. Similarly, recordings from cell-attached patches of the apical membrane of surface cells surrounding the openings of distal colonic crypts revealed identical K+ channels in 1 of 11 (9%) patches in control animals, and in 9 of 13 (69%) patches in K(+)-loaded animals. 3. In isolated surface cells and surface cells in situ, K+ channels had mean slope conductances of 209 +/- 6 and 233 +/- 14 pS, respectively, when inside-out patches were bathed symmetrically in K2SO4 solution. The channels were sensitive to 'cytosolic' Ca2+ concentration, were voltage sensitive at 'cytosolic' Ca2+ concentrations encountered in colonic epithelial cells, and were inhibited by 1 mM quinidine, 20 mM TEA or 5 mM Ba2+ ions. 4. The data show that dietary K+ loading increases the abundance of Ca(2+)- and voltage-sensitive large-conductance K+ channels in the apical membrane of surface cells in rat distal colon. These channels constitute the enhanced macroscopic apical K+ conductance previously identified in these cells, and are likely to play a critical role in the active K+ secretory process that typifies this model of colonic K+ adaptation.

Adaptation, Physiological↗
PubMed1994

Rundown and reactivation of ATP-sensitive potassium channels (KATP) in mouse skeletal muscle.

Dissociated single fibers from the mouse flexor digitorum brevis (FDB) muscle were used in patch clamp experiments to investigate the mechanisms of activation and inactivation of KATP in mammalian skeletal muscle. Spontaneous rundown of channel activity, in many excised patches, occurred gradually over a period of 10-20 min. Application of 1.0 mM free-Ca2+ to the cytoplasmic side of the patch caused irreversible inactivation of KATP within 15 sec. Ca(2+)-induced rundown was not prevented by the presence of 1.0 microM okadaic acid or 2.0 mg ml-1 of an inhibitor of calcium-activated neutral proteases, a result consistent with the conclusion that phosphatases or calcium-activated neutral proteases were not involved in the rundown process. Application of 1.0 mM Mg.ATP to Ca(2+)-inactivated KATP caused inhibition of residual activity but little or no reactivation of the channels upon washout of ATP, even in the presence of the catalytic subunit of cyclic AMP-dependent protein kinase (10 U ml-1). Mg.ATP also failed to reactivate KATP, even after only partial spontaneous rundown, despite the presence of channels that could be activated by the potassium channel opener BRL 38227. Nucleotide diphosphates (500 microM; CDP, UDP, GDP and IDP) caused immediate and reversible opening of Ca(2+)-inactivated KATP. Reactivation of KATP by ADP (100 microM) increased further upon removal of the nucleotide. In contrast to KATP from cardiac and pancreatic cells, there was no evidence for phosphorylation of KATP from the surface sarcolemma of dissociated single fibers from mouse skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed2006

Development of synapses and expression of a voltage-gated potassium channel in chick embryonic auditory nuclei.

The potassium channel protein, Kv3.1, is abundantly expressed in the chick auditory pathway. Its b-isoform is found in nucleus magnocellularis, which receives the cochlear input, both before and after the establishment of synaptic connections. It is also present in cell cultures in the absence of any peripheral input. However, the expression of this isoform in the embryo has been shown to increase with development. Here, we address the question of the correlation between maturation of synapses in the auditory pathway and the pattern of expression of the b-isoform in a series of embryos prepared for immunohistochemistry at Hamburger-Hamilton stages equivalent to E10, E12, E14, and E17. We show here that this subunit translocates from the perinuclear cytoplasm to the cell membrane domain in nucleus magnocellularis at the time that cochlear nerve endings emerge as endbulbs of Held (E17). In nucleus laminaris, by this time, while abundant Kv3.1b occurs in the perinuclear cytoplasm, a translocation to the cell membrane domain has not yet occurred, and the mature peri-synaptic localization is delayed to a later stage. This difference suggests a hierarchy in the developmental expression of Kv3.1. An unexpected finding is the expression of the a-isoform of Kv3.1 in astrocytes, especially those which surround the developing nuclei and their connecting fibers. We also report here for the first time the presence of Kv3.1b in the initial segments of axons at the times when they begin to form. Our observations suggest that the Kv3.1 channel protein is regulated through mechanisms linked to the development of synaptic activity.

Animals↗
PubMed1993

Arteriolar tone is determined by activity of ATP-sensitive potassium channels.

The role of ATP-sensitive potassium channels (KATP) in determining resting arteriolar tone and vasodilator reactivity was assessed in superfused, hamster microcirculatory beds studied via intravital microscopy. Under resting conditions, the selective KATP blocker, glibenclamide, produced concentration-dependent vasoconstriction in both the cheek pouch and the cremaster muscle. Concentration-related constriction of cheek pouch arterioles was also observed with tetrapentylammonium, although this agent appeared to have toxic effects on the microcirculation. Glibenclamide (2 microM) abolished arteriolar vasodilation to cromakalim and pinacidil over a concentration range (10 nM-1 microM) in which these agents are selective KATP agonists and also significantly inhibited adenosine-, carbacyclin-, and isoproterenol-induced vasodilation. In contrast, responses to other vasodilators were not significantly affected [methacholine, forskolin, and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP)] or only slightly depressed (sodium nitroprusside). Thus the activity of KATP determines, in part, resting arteriolar tone in the hamster. Furthermore, vasodilators like adenosine, beta-adrenergic agonists, and prostacyclin appear to act through these ion channels by a mechanism that may not involve cAMP.

Adenosine Triphosphate↗
PubMed2003

Kir2 potassium channels in rat striatum are strategically localized to control basal ganglia function.

Parkinson's disease is the most frequent movement disorder caused by loss of dopaminergic neurons in the midbrain. Intentions to avoid side effects of the conventional therapy should aim to identify additional targets for potential pharmacological intervention. In principle, every step of a signal transduction cascade such as presynaptic transmitter release, type and occupation of postsynaptic receptors, G protein-mediated effector mechanisms, and the alterations of pre- or postsynaptic potentials as determined by the local ion channel composition, have to be considered. Due to their diversity and their widespread but distinct localizations, potassium channels represent interesting candidates for new therapeutic strategies. As a first step, the present report aimed to study in the striatum the cellular and subcellular distribution of the individual members of the Kir2 family, a group of proteins forming inwardly rectifying potassium channels. For this purpose polyclonal monospecific affinity-purified antibodies against the less conserved carboxyterminal sequences from the Kir2.1, Kir2.2, Kir2.3, and Kir2.4 proteins were prepared. All subunits of the Kir2 family were detected on somata and dendrites of most striatal neurons. However, the distribution of two of them was not homogeneous. Striatal patch areas were largely devoid of the Kir2.3 protein, and the Kir2.4 subunit was most prominently expressed on the tonically active, giant cholinergic interneurons of the striatum. These two structures are among the key players in regulating dopaminergic and cholinergic neurotransmission within the striatum, and therefore are of major importance for the output of the basal ganglia. The heterogeneous localization of the Kir2.3 and the Kir2.4 subunits with respect to these strategic structures pinpoints to these channel proteins as promising targets for future pharmacological efforts.

Acetylcholine↗
PubMed1994

The effect of ATP-sensitive potassium channel modulation on heart rate in isolated muskrat and guinea pig hearts.

Muskrats (Ondontra zibethicus) are common freshwater diving mammals exhibiting a bradycardia with both forced and voluntary diving. This bradycardia is mediated by vagal innervation; however, if hypoxia is present there may be local factors that also decrease heart rate. Some of these local factors may include ATP-sensitive potassium channel activation and extracellular accumulation of potassium ions, hydrogen ions and lactate. The purpose of this study was to investigate the role of these factors in the isolated perfused hearts of muskrats and of a non-diving mammal, the guinea pig. Although lactate and proton administration reduced heart rate in isolated muskrat and guinea pig hearts, there was no difference in the response to lactate and proton infusion between the two species. Muskrat hearts were more sensitive to the heart-rate-lowering effects of exogenously applied potassium than were guinea pig hearts. Early increases in extracellular potassium concentration during hypoxia are thought to be mediated by the ATP-sensitive potassium channel. Activation of these channels under normoxic conditions had a mildly negative chronotropic effect in both species; however, activation of these channels with Lemakalim under hypoxic conditions caused the guinea pig heart to respond with an augmented bradycardia similar to that seen in the hypoxic muskrat heart in the absence of drugs. Inhibition of these channels by glibenclamide during hypoxia was partially successful in blocking the bradycardia in guinea pig hearts, but inhibition of the same channels in hypoxic muskrat hearts had a damaging effect as two of five hearts went into contracture during the hypoxia. Thus, although ATP-sensitive potassium channels appear to have a major role in the bradycardia of hypoxia in guinea pigs, the failure to prevent the bradycardia by inhibition of these channels in muskrat hearts suggests that multiple factors are involved in the hypoxia-induced bradycardia in this species.

Adenosine Triphosphate↗
PubMed2002

Small conductance calcium-activated potassium channels of trout CNS: molecular structure, developmental expression, and partial biophysical characterization.

Two small conductance calcium-activated potassium channels that exhibited amino acid similarity with mammalian SK2 and SK3, respectively, were PCR cloned from the CNS of trout and sequenced. Upon heterologous expression in Sf21 insect cells trout SK2 (termed tSK2) produced a calcium-dependent, voltage-insensitive, and non-inactivating current with a single unit conductance of about 11 pS. This current was half maximally activated by 0.76 microM Ca(2+) and blocked by picomolar concentrations of apamin but not by TEA. Transcripts of both SK-related channels possessed a widespread distribution in the mature brain tissue of trout and outside the nervous system were detectable in muscle tissue as well as in liver. As revealed by RT-PCR analysis transcripts encoding tSK2 and tSK3 channels were early detectable during brain development (stage 30, shortly after hatching).

Animals↗
PubMed1993

mSlo, a complex mouse gene encoding "maxi" calcium-activated potassium channels.

Complementary DNAs (cDNAs) from mSlo, a gene encoding calcium-activated potassium channels, were isolated from mouse brain and skeletal muscle, sequenced, and expressed in Xenopus oocytes. The mSlo-encoded channel resembled "maxi" or BK (high conductance) channel types; single channel conductance was 272 picosiemens with symmetrical potassium concentrations. Whole cell and single channel currents were blocked by charybdotoxin, iberiotoxin, and tetraethylammonium ion. A large number of variant mSlo cDNAs were isolated, indicating that several diverse mammalian BK channel types are produced by a single gene.

Alternative Splicing↗
PubMed1990

The oral hypoglycemic agent, U-56324, inhibits the activity of ATP-sensitive potassium channels in cell-free membrane patches from cultured mouse pancreatic B-cells.

U-56324, a hypoglycemic agent derived from nicotinic acid, inhibited the activity of ATP-sensitive potassium channels in excised patches from mouse pancreatic B-cells. The effect of U-56324 on channel activity was reversible and concentration-dependent while it had no effect on single channel conductance. The positional isomer, U-59588, which has relatively little hypoglycemic activity, had no effect on channel properties. U-56324, at the same concentrations, had no effect on calcium-activated potassium channels. The basis for the potentially antidiabetic properties of U-56324 may therefore be due to direct and specific inhibition of ATP-sensitive potassium channels.

Adenosine Triphosphate↗
PubMed1990

Potassium channel openers and vascular smooth muscle relaxation.

Potassium channel openers comprise a diverse group of chemical agents which open plasma-lemmal K-channels. They show selectivity for smooth muscle, although K-channels in cardiac and skeletal muscle, neurones and the pancreatic beta-cell are also affected at relatively high concentrations. In addition, at least one endogenous K-channel opener of vascular origin--endothelium-derived hyperpolarizing factor--exists and in man plays a role in modulating blood vessel tone. The type of K-channel involved in the actions of both exogenous and endogenous K-channel openers is still uncertain, although a prime candidate in smooth muscle seems similar to the [ATPi]-modulated K-channel in the pancreatic beta-cell. This review focuses attention on the action of these agents in vascular smooth muscle and on the possible clinical exploitation of their powerful vasorelaxant properties.

Animals↗
PubMed2003

Isoflurane sensitizes the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel to pinacidil.

BACKGROUND: Cardioprotective effects of isoflurane are partially mediated by the sarcolemmal adenosine triphosphate-sensitive potassium (sarcK ATP ) channel. The authors tested the hypothesis that isoflurane sensitizes sarcK ATP channels to a potassium channel opener, pinacidil, adenosine- and phospholipid-mediated pathways. METHODS: Activation by pinacidil of the K ATP current (I KATP ) was monitored in guinea pig ventricular myocytes at 0.5 and 5 mm intracellular ATP in the whole cell configuration of the patch clamp technique. The sensitization effect was evaluated by pretreating each myocyte with isoflurane (0.57 +/- 0.04 mm) before application of pinacidil (5 micro m) in the continued presence of the anesthetic. To investigate whether intracellular signaling pathways may be involved in isoflurane sensitization, the authors used the adenosine receptor antagonist theophylline (100 micro m) and the phosphatidylinositol kinase inhibitor wortmannin (100 micro m). RESULTS: The density of pinacidil-activated I KATP was higher at 0.5 mm ATP (20.7 +/- 3.2 pA/pF) than at 5 mm ATP (2.0 +/- 0.3 pA/pF). At 0.5 mm ATP, pretreatment with isoflurane caused an increase in density of pinacidil-activated I KATP (42.4 +/- 6.2 pA/pF) and accelerated the rate of current activation (from 5.4 +/- 1.2 to 39.0 +/- 7.9 pA. pF(-1). min(-1) ). Theophylline attenuated current activation by pinacidil (9.4 +/- 3.9 pA/pF) and abolished the sensitization effect of isoflurane on I KATP (10.0 +/- 2.5 pA/pF). Wortmannin did not alter pinacidil activation of I KATP (13.2 +/- 1.7 pA/pF) but prevented sensitization by isoflurane (15.8 +/- 4.5 pA/pF). CONCLUSIONS: These results suggest that isoflurane increases sensitivity of cardiac sarcK ATP channels to the potassium channel opener pinacidil. Blockade of adenosine receptors or phosphatidylinositol kinases abolishes the sensitization effect, suggesting that the adenosine and phospholipid signaling pathways may be involved in the actions by isoflurane.

ATP-Binding Cassette Transporters↗
PubMed1994

Cloning and expression of a family of inward rectifier potassium channels.

Five new members of the two-transmembrane domain potassium channel family have been identified from rat brain, heart and skeletal muscle. The channel mRNAs are differentially expressed and found in both the central nervous system and periphery. Expression of two of these channels in Xenopus oocytes gave rise to inwardly rectifying potassium currents which were voltage-dependently blocked by barium and cesium. Voltage command pulses negative to Ek evoked inward currents which rapidly reached a peak amplitude and relaxed to a steady-state level. The quantity of current relaxation differed in the two channels and was increased at more negative potentials. The degree of current rectification was also different for the two channels. The results demonstrate the existence of a large and widely expressed family of inward rectifier potassium channel subunits with distinct tissue distributions and functional properties.

Amino Acid Sequence↗
PubMed1998

Structure-activity relationships of the Kvbeta1 inactivation domain and its putative receptor probed using peptide analogs of voltage-gated potassium channel alpha- and beta-subunits.

Certain beta-subunits exert profound effects on the kinetics of voltage-gated (Kv) potassium channel inactivation through an interaction between the amino-terminal "inactivation domain" of the beta-subunit and a "receptor" located at or near the cytoplasmic mouth of the channel pore. Here we used a bacterial random peptide library to examine the structural requirements for this interaction. To identify peptides that bind Kv1.1 we screened the library against a synthetic peptide corresponding to the predicted S4-S5 cytoplasmic loop of the Kv1.1 alpha-subunit (residues 313-328). Among the highest affinity interactors were peptides with significant homology to the amino terminus of Kvbeta1. We performed a second screen using a peptide from the amino terminus of Kvbeta1 (residues 2-31) as "bait" and identified peptide sequences with significant homology to the S4-S5 loop of Kv1.1. A series of synthetic peptides containing mutations of the wild-type Kvbeta1 and Kv1.1 sequences were examined for their ability to inhibit Kvbeta1/Kv1.1 binding. Amino acids Arg20 and Leu21 in Kvbeta1 and residues Arg324 and Leu328 in Kv1.1 were found to be important for the interaction. Taken together, these data provide support for the contention that the S4-S5 loop of the Kv1.1 alpha subunit is the likely acceptor for the Kvbeta1 inactivation domain and provide information about residues that may underlie the protein-protein interactions responsible for beta-subunit mediated Kv channel inactivation.

Amino Acid Sequence↗
PubMed1993

Influence of epithelium on the inhibition of melittin-induced contraction of guinea-pig isolated trachea by the potassium channel opener NIP-121.

1. We have investigated the effect of the potassium channel opener, NIP-121, on contraction elicited by melittin (a phospholipase A2 activator) in epithelium-intact and epithelium-denuded trachea isolated from guinea-pigs. The effects of NIP-121 were compared with those of isoprenaline, aminophylline and hydrocortisone. 2. In the presence of the cyclo-oxygenase inhibitor, indomethacin (5 microM), melittin (3 micrograms ml-1) caused time-dependent contraction. The melittin-induced contractile response was significantly augmented by removal of the epithelium and was concentration-dependently and completely inhibited by the phospholipase A2 (PLA2) inhibitor, p-bromophenacyl bromide (BPB 10-100 microM), and the lipoxygenase inhibitor, phenidone (10-300 microM). Similar inhibition of the melittin response by BPB (10 microM) and phenidone (10 microM) was observed in the epithelium-denuded trachea. 3. Concentration-dependent inhibition of the melittin response was induced by preincubation with NIP-121 (0.03 and 0.1 microM), isoprenaline (0.001 and 0.01 microM), aminophylline (30 and 100 microM) and hydrocortisone (100 and 300 microM). The effect of NIP-121 was abolished by glibenclamide (1 microM). 4. The inhibitory effect of NIP-121 on the melittin response was greatly reduced by removing the epithelium while that of the isoprenaline, aminophylline or hydrocortisone was not changed. 5. The inhibition of the melittin response by these drugs was similar to their inhibition of the contraction elicited by a low concentration (3 nM) of leukotriene D4 (LTD4) in the epithelium-intact trachea. Inhibition of the LTD4 response by NIP-121 was not observed in the epithelium-denuded trachea. However, higher concentrations of NIP-121 (0.3 and 1 microM) did inhibit LTD4-induced contractions of epithelium-denuded trachea.6. These findings suggest that melittin causes epithelium-dependent contraction of the guinea-pig isolated trachea which is mediated by products of lipoxygenase activity. NIP-121 may inhibit the melittin response by activating glibenclamide-sensitive potassium channels, which appear to be epithelium-dependent (an indirect effect of NIP-121 apart from its direct effect on the airway smooth muscle) while isoprenaline, aminophylline and hydrocortisone act directly to relax the trachealis smooth muscle.

Aminophylline↗
PubMed1994

Potassium channels: a computer prediction of structure and selectivity.

Model structures for the pore of the potassium channels Shaker and ROMK1 are predicted. The models arise from computer simulations and suggest reasons for the striking selectivity of these channels for K+ and the blocking of ROMK1 by internal Mg2+. The modelled structure of the Shaker pore is supported by mutagenesis data. The mutagenesis experiments indicate the side chains responsible for binding to blocking agents [tetraethylammonium (TEA) and charybdotoxin (CTX)] and the model has these side chains suitably oriented for binding. An aromatic K+ binding site part way down the pore is also predicted by the Shaker pore model.

Amino Acid Sequence↗
PubMed1998

Ion permeation through a G-protein activated (GIRK1/GIRK5) inwardly rectifying potassium channel.

In order to further investigate a G-protein activated inwardly rectifying potassium channel subunit, GIRK1 was expressed in Xenopus oocytes (where it coassembles with the endogenous GIRK5). The mechanism underlying ion permeation and rectification were measured in isolated inside-out patches. Single channel current amplitudes under symmetrical K+ concentrations at different holding potentials were evaluated. Inward-rectification of K+-currents through open GIRK1/GIRK5 channels was removed by washing out polyamines and Mg2+ ions. We developed a simple 'two-sites-three-barrier' (2S3B) Eyring rate theory model of K+ ion permeation for GIRK1/GIRK5 channels. The resulting optimized parameter-set will be used as a working model for subsequent investigation regarding K+ permeation process through the GIRK1/GIRK5 channel.

Animals↗
PubMed2002

Intrinsic flexibility and gating mechanism of the potassium channel KcsA.

The gating mechanism of the potassium channel KcsA was studied by normal mode analysis. The results provided an atomic description of the locations of the pivot points and the motional features of key structural elements in the gating process. Two pivot points were found in the motions of the inner TM2 helical bundle that directly modulate the size of the central channel pore. One point is an intrasubunit hinge point that sharply divides the structural flexibility between the more rigid selectivity filter and the more mobile peripheral transmembrane helices. Such a division is vital for KcsA because it permits the large-scale motions of transmembrane helices required for the gating and, in the meantime, maintains the rigidity of the filter region essential for the selectivity. The other pivot point is an intersubunit one at which all four TM2 helices are bundled together. During the gating process, each TM2 helix undergoes a lever-like swinging motion pivoting on the intrasubunit hinge, and the entire TM2 bundle undergoes a concerted rotational motion around the central channel axis constrained around the intersubunit bundle point. This series of motions leads to a dramatic enlargement of the intracellular gate without loosening up the structural integrity.

Bacterial Proteins↗