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PubMed1999

Small-conductance calcium-activated potassium channels.

SK channels play a fundamental role in all excitable cells. SK channels are potassium selective and are activated by an increase in the level of intracellular calcium, such as occurs during an action potential. Their activation causes membrane hyperpolarization, which inhibits cell firing and limits the firing frequency of repetitive action potentials. The intracellular calcium increase evoked by action potential firing decays slowly, allowing SK channel activation to generate a long-lasting hyperpolarization termed the slow afterhyperpolarization (sAHP). This spike-frequency adaptation protects the cell from the deleterious effects of continuous tetanic activity and is essential for normal neurotransmission. Slow AHPs can be classified into two groups, based on sensitivity to the bee venom toxin apamin. In general, apamin-sensitive sAHPs activate rapidly following a single action potential and decay with a time constant of approximately 150 ms. In contrast, apamin-insensitive sAHPs rise slowly and decay with a time constant of approximately 1.5 s. The basis for this kinetic difference is not yet understood. Apamin-sensitive and apamin-insensitive SK channels have recently been cloned. This chapter will compare with different classes of sAHPs, discuss the cloned SK channels and how they are gated by calcium ions, describe the molecular basis for their different pharmacologies, and review the possible role of SK channels in several pathological conditions.

Action Potentials↗
PubMed2004

Inhibition of ROMK potassium channel by syntaxin 1A.

ROMK potassium channels are present in the cortical collecting duct (CCD) of the kidney and serve as apical exit pathways for K+ secretion in this nephron segment. K+ secretion in the CCD is regulated by multiple factors. In this study, we show that syntaxin 1A, but not syntaxin 3 or 4, inhibited whole cell ROMK currents in Xenopus laevis oocytes. Syntaxin 1A, but not syntaxin 3 or 4, interacted with the COOH-terminal cytoplasmic domain of ROMK in intro. Coexpression with synaptobrevin 2 reversed inhibition of whole cell ROMK currents by syntaxin 1A. In excised inside-out membranes of oocytes, application of fusion proteins containing the cytoplasmic region of syntaxin 1A to the cytoplasmic face caused a dose-dependent inhibition of ROMK. We further examined regulation of the K+ channels in the CCD by syntaxin 1A. Application of botulinum toxin C1 to the excised inside-out membranes of the CCD caused an increase in the activity of K+ channels. In contrast, application of toxin B had no effects. These results suggest that syntaxin 1A causes a tonic inhibition of the K+ channels in the apical membrane of the CCD. Binding of synaptobrevin 2 to syntaxin 1A during docking and fusion of transport vesicles to the plasma membranes of CCD may lead to activation of these channels.

Animals↗
PubMed2003

Central sympathetic chemosensitivity and Kir1 potassium channels in the cat.

The possible involvement of potassium channels in central chemosensitivity, with special reference to the Kir1.1 potassium channel, was investigated by studying the CO(2) response of presympathetic neurons in the rostroventrolateral medulla (RVLM) in the absence or presence of various K(+) channel inhibitors. Synaptic input to RVLM neurons was blocked by local injection of omega-agatoxin and omega-conotoxin. Activity of RVLM neurons was measured by recording the electrical activity in preganglionic (WR-T(3)) or postganglionic (renal) sympathetic nerves after perfusion of the lower brainstem via the left vertebral artery with CO(2)-enriched saline solution. Unspecific K(+) channel blockade by BaCl(2) reduced the excitatory response of sympathetic activity after CO(2)-perfusion to 56% of control. A quantitatively similar inhibition of the central CO(2) response was obtained after administration of 9-fluorenylmethylchloroformate (FMOC-Cl) which eliminates pH sensitivity of Kir1 and Kir4.1. Furthermore, two structurally different Kir1 inhibiting toxins, tertiapin and Lq2, also reduced the central CO(2) response to approximately 50% of control. In contrast, charybdotoxin (CTX) had no effect on the CO(2) response. Using RT-PCR the expression of mRNA homologous to rat Kir1 mRNA was identified in the cat medulla oblongata. These data suggest that a modulation of potassium channel activity possibly via Kir1 may contribute to central chemosensitivity.

Animals↗
PubMed2000

Sensitivity of native and cloned hippocampal delayed-rectifier potassium channels to verapamil.

The effects of the phenylalkylamine verapamil on native and cloned hippocampal voltage-operated potassium channels were investigated. Native channels were studied in acutely isolated CA1 neurons from the guinea pig with the whole-cell patch-clamp technique. Cloned channels were expressed in oocytes of Xenopus laevis and studied with the two-electrode voltage-clamp technique. Native potassium channels: Verapamil suppressed the potassium currents in micro- and submicromolar concentrations. The current suppression increased during the voltage step. The IC50 value of verapamil was 3 micromol/l and the Hill coefficient was 0.5 indicating a mixed population of potassium channels with distinct verapamil sensitivity. Cloned potassium channels: The hippocampal potassium channels Kv1.1, Kv1.2, Kv1.3, Kv2.1, Kv3.1 and Kv3.2 were affected by verapamil in micromolar concentrations. The effect increased with depolarization time, was voltage-dependent, reached 90% of the maximum within around 40 s after start of verapamil application, recovered slowly after wash-out and did not reach control values even after wash-out times of six minutes. The IC50 values differed markedly and were 35 micromol/l for the Kv1.1 channel, 98 micromol/l for the Kv1.2 channel, 12 micromol/l for the Kv1.3 channel, 226 micromol/l for the Kv2.1 channel, 6 micromol/l for the Kv3.1 channel and 11 micromol/l for the Kv3.2 channel.

Animals↗
PubMed2006

KCNE3 is an inhibitory subunit of the Kv4.3 potassium channel.

The mammalian Kv4.3 potassium channel is a fast activating and inactivating K+ channel widely distributed in mammalian tissues. Kv4.3 is the major component of various physiologically important currents ranging from A-type currents in the CNS to the transient outward potassium conductance in the heart (I(to)). Here we show that the KCNE3 beta-subunit has a strong inhibitory effect on current conducted by heterologously expressed Kv4.3 channels. KCNE3 reduces the Kv4.3 current amplitude, and it slows down the channel activation and inactivation as well as the recovery from inactivation. KCNE3 also inhibits currents generated by Kv4.3 in complex with the accessory subunit KChIP2. We find the inhibitory effect of KCNE3 to be specific for Kv4.3 within the Kv4 channel family. Kv4.3 has previously been shown to interact with a number of beta-subunits, but none of the described subunit-interactions exert an inhibitory effect on the Kv4.3 current.

Animals↗
PubMed2001

The dipole moment of membrane proteins: potassium channel protein and beta-subunit.

The mechanism of ion channel opening is one of the most fascinating problems in membrane biology. Based on phenomenological studies, early researchers suggested that the elementary process of ion channel opening may be the intramembrane charge movement or the orientation of dipolar proteins in the channel. In spite of the far reaching significance of these hypotheses, it has not been possible to formulate a comprehensive molecular theory for the mechanism of channel opening. This is because of the lack of the detailed knowledge on the structure of channel proteins. In recent years, however, the research on the structure of channel proteins made marked advances and, at present, we are beginning to have sufficient information on the structure of some of the channel proteins, e.g. potassium-channel protein and beta-subunits. With these new information, we are now ready to have another look at the old hypothesis, in particular, the dipole moment of channel proteins being the voltage sensor for the opening and closing of ion channels. In this paper, the dipole moments of potassium channel protein and beta-subunit, are calculated using X-ray diffraction data. A large dipole moment was found for beta-subunits while the dipole moment of K-channel protein was found to be considerably smaller than that of beta-subunits. These calculations were conducted as a preliminary study of the comprehensive research on the dipolar structure of channel proteins in excitable membranes, above all, sodium channel proteins.

Animals↗
PubMed1995

Different calcium channels are coupled to potassium channels with distinct physiological roles in vagal neurons.

Whole-cell and sharp microelectrode recordings were obtained from neurons of rat dorsal motor nucleus of the vagus (DMV) in transverse slices of the rat medulla maintained in vitro. Calcium currents were studied with sodium currents blocked with tetrodotoxin, potassium currents blocked by perfusing the cell with caesium as the main cation and using barium as the charge carrier. From a holding potential of -60 mV, inward currents activated at potentials positive of -50 mV and peaked around 0 mV. Voltage clamping the neuron at more hyperpolarised potentials did not reveal any low-threshold inward current. The inward current was effectively blocked by cadmium (100 microM) and nicked (1 mM), suggesting that it is carried by voltage-dependent calcium channels. The inward current could be separated into three pharmacologically distinct components: 40% of the whole cell current was omega-conotoxin sensitive; 20% of the current was nifedipine sensitive; and the rest was blocked by high concentrations of cadmium and nickel. This remaining current cannot be due to P-type calcium channels as omega-agatoxin had no effect on the inward current. Nifedipine had no significant effect on the action potential. Application of omega-conotoxin reduced the calcium component of the action potential and significantly reduced the potassium current underlying the afterhyperpolarization. Application of charybdotoxin slowed action potential repolarization. When N-type calcium channels were blocked with omega-conotoxin, charybdotoxin was still effective in slowing repolarization. In contrast, charybdotoxin was ineffective ineffective when calcium influx was blocked with the non-specific calcium channel blocker cadmium.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMedDate not supplied

Nitric oxide donors mediate vasodilation in human placental arteries partly through a direct effect on potassium channels.

We have investigated the involvement of potassium channels in the NO-induced relaxation of small ET-1 precontracted arteries from placentas of normal pregnancies in the presence of the potassium channel modulating agents charybdotoxin, 4-AP, glibenclamide, TEA and the blocker of soluble guanylyl cyclase, ODQ, respectively. We have studied the effect of the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) in vessels precontracted by different concentrations of potassium and we have also investigated the presence of BK(Ca) channels in placental arteries by immunohistochemistry and immunoblotting. Our results show that charybdotoxin, an inhibitor of large- and intermediate-conductance Ca(2+)-activated potassium channels, inhibits relaxation in placental arteries. In presence of both charybdotoxin and ODQ, the inhibition of relaxation was significantly stronger, which indicates that NO-induced relaxation of human placental arteries is partly mediated through cGMP, and partly through a direct effect on potassium channels of the BK(Ca) type. The NO-donor SNAP preferentially relaxes contractions induced by 75 mM K(+) as compared to 100 mM K(+). This effect profile is a unique feature of drugs acting by K(+) channel opening. The immunohistochemistry shows that BK(Ca) channels are located both in smooth muscle and in endothelium in placental arteries.

Adult↗
PubMed1997

An immunocytochemical study on the distribution of two G-protein-gated inward rectifier potassium channels (GIRK2 and GIRK4) in the adult rat brain.

G-protein-gated inward rectifier potassium channels mediate the synaptic actions of numerous neurotransmitters in the mammalian brain, and were recently shown to be candidates for genetic mutations leading to neuronal cell death. This report describes the localization of G-protein-gated inward rectifier potassium channel-2 and G-protein-gated inward rectifier potassium channel-4 proteins in the rat brain, as assessed by immunocytochemistry. G-protein-gated inward rectifier potassium channel-2 immunoreactivity was widely distributed throughout the brain, with the strongest staining seen in the hippocampus, septum, granule cell layer of the cerebellum, amygdala and substantia nigra pars compacta. In contrast, G-protein-gated inward rectifier potassium channel-4 immunoreactivity was restricted to some neuronal populations, such as Purkinje cells and neurons of the globus pallidus and the ventral pallidum. The presence of G-protein-gated inward rectifier potassium channel-2 immunoreactivity in substantia nigra pars compacta dopaminergic neurons was confirmed by showing its co-localization with tyrosine hydroxylase by double immunocytochemistry, and also by selectively lesioning dopaminergic neurons with the neurotoxin 6-hydroxydopamine. At the cellular level both proteins were localized in neuronal cell bodies and dendrites, but clear differences were seen in the degree of dendritic staining among neuronal groups. For some neuronal groups the staining of distal dendrites (notably dendritic spines) was strong, while for others the cell body and proximal dendrites were preferentially labelled. In addition, some of the results suggest that G-protein-gated inward rectifier potassium channel-2 protein could be localized in distal axonal terminal fields. A knowledge of the distribution of G-protein-gated inward rectifier potassium channel proteins in the brain could help to elucidate their physiological roles and to evaluate their potential involvement in neurodegenerative processes in animal models and human diseases.

Animals↗
PubMed1999

Voltage-gated potassium channels: from hyperexcitability to excitement.

The superfamily of voltage-activated potassium channels may express structurally and functionally diverse voltage-activated potassium channels in the nervous system. The roles of some voltage-activated potassium channel types, e.g. rapidly inactivating (transiently active type) channels and muscarine sensitive muscarine sensitive channels, are beginning to be understood. They may significantly influence dendritic action-potential back-propagation, signal to noise ratios in presynaptic excitability or the responsiveness of a neuron to synaptic input. Inherited disorders related to changes in excitability (episodic ataxia, epilepsy, heart arrhythmia) or to defects in sensory perception (hearing loss) have been associated with mutations in a few voltage-activated potassium channel genes. Most likely, more voltage-activated potassium channel genes will be linked to related disorders in the near future.

Animals↗
PubMed1991

Effect of potassium channel blockade on the anti-ischemic actions of mechanistically diverse agents.

The ATP-sensitive potassium channel opener, cromakalim, protects ischemic hearts and its effect can be reversed by glyburide. It is presently unknown if glyburide can abolish the anti-ischemic effects of mechanistically different agents or if blockers of other potassium channels can abolish the protective effects of cromakalim. Thus, the effect of glyburide on previously reported cardioprotective agents was tested in globally ischemic/reperfused isolated rat hearts. Calcium antagonists, sodium channel blockers and calmodulin antagonists were found to significantly improve postischemic contractile function and reduce lactate-dehydrogenase release after 25 min of global ischemia and 30 min of reperfusion. Glyburide did not reverse their cardioprotective effects. 5-(N,N-dimethyl)amiloride, an inhibitor of Na+/H+ exchange, significantly reduced lactatedehydrogenase release without improving postischemic contractile function, and glyburide did not reverse this. The potassium channel opener, cromakalim, protected ischemic rat hearts (improved recovery of contractile function and reduced enzyme release) and this was abolished by glyburide. Charybdotoxin blocks both calcium-activated potassium channels and voltage-gated potassium channels and E-4031 the delayed rectifier potassium channels. Neither was found to effect the action of the potassium channel opener, cromakalim. These data indicate that glyburide is selective in that it only blocks the anti-ischemic effects of potassium channel openers and not other cardioprotective compounds. In addition, cromakalim is unaffected by blockers of other potassium channels, further indicating selectivity of glyburide for ATP-sensitive potassium channels.

Animals↗
PubMed1999

Domains responsible for constitutive and Ca(2+)-dependent interactions between calmodulin and small conductance Ca(2+)-activated potassium channels.

Small conductance Ca(2+)-activated potassium channels (SK channels) are coassembled complexes of pore-forming SK alpha subunits and calmodulin. We proposed a model for channel activation in which Ca2+ binding to calmodulin induces conformational rearrangements in calmodulin and the alpha subunits that result in channel gating. We now report fluorescence measurements that indicate conformational changes in the alpha subunit after calmodulin binding and Ca2+ binding to the alpha subunit-calmodulin complex. Two-hybrid experiments showed that the Ca(2+)-independent interaction of calmodulin with the alpha subunits requires only the C-terminal domain of calmodulin and is mediated by two noncontiguous subregions; the ability of the E-F hands to bind Ca2+ is not required. Although SK alpha subunits lack a consensus calmodulin-binding motif, mutagenesis experiments identified two positively charged residues required for Ca(2+)-independent interactions with calmodulin. Electrophysiological recordings of SK2 channels in membrane patches from oocytes coexpressing mutant calmodulins revealed that channel gating is mediated by Ca2+ binding to the first and second E-F hand motifs in the N-terminal domain of calmodulin. Taken together, the results support a calmodulin- and Ca(2+)-calmodulin-dependent conformational change in the channel alpha subunits, in which different domains of calmodulin are responsible for Ca(2+)-dependent and Ca(2+)-independent interactions. In addition, calmodulin is associated with each alpha subunit and must bind at least one Ca2+ ion for channel gating. Based on these results, a state model for Ca2+ gating was developed that simulates alterations in SK channel Ca2+ sensitivity and cooperativity associated with mutations in CaM.

Animals↗
PubMed1999

Simultaneous binding of two protein kinases to a calcium-dependent potassium channel.

Large-conductance calcium-dependent potassium channels are subject to modulation by protein kinases, phosphatases, and other signaling proteins, and it has been inferred from electrophysiological experiments that signaling proteins sometimes can be intimately associated with these channels in a regulatory complex. We show here that endogenous protein kinase activity coimmunoprecipitates with both native and recombinant Drosophila Slowpoke (dSlo) calcium-dependent potassium channels. Coimmunoprecipitation experiments using antibodies against several protein kinases demonstrate that dSlo can bind simultaneously to the Src tyrosine kinase and to the catalytic subunit of the cAMP-dependent protein kinase (PKAc). Both kinases can phosphorylate the channel in Drosophila heads and in heterologous host cells. The PKAc binds directly to a 172-amino acid region in the C-terminal domain of dSlo, without the intervention of regulatory subunits or anchoring proteins, and channel phosphorylation by PKAc is not required for this binding interaction. In contrast, several phosphorylatable tyrosine residues in dSlo are important for Src binding. The results are consistent with the idea that an ion channel can act as a scaffold for its own specific set of modulatory enzymes.

Animals↗
PubMed1993

Potassium channel activators in vasospastic angina.

Activation of potassium channels induces relaxation of vascular smooth muscle, and experimental studies have demonstrated that potassium channel activators have potent coronary vasodilator properties. In humans, nicorandil, a potassium channel blocker, causes vasodilatation not only in angiographically normal segments but also at sites of dynamic coronary stenosis, where coronary spasm has been provoked by methylergometrine as well as at sites of spontaneous spasm. The efficacy of nicorandil in relieving ergometrine-induced spasm is comparable to that of nifedipine. Oral administration of nicorandil significantly reduces the frequency of anginal episodes in patients with vasospastic angina, and either as monotherapy, or in conjunction with other agents is a novel therapeutic option in patients with vasospastic angina.

Angina Pectoris, Variant↗
PubMed1998

The conduction pore of a cardiac potassium channel.

Ion channels form transmembrane water-filled pores that allow ions to cross membranes in a rapid and selective fashion. The amino acid residues that line these pores have been sought to reveal the mechanisms of ion conduction and selectivity. The pore (P) loop is a stretch of residues that influences single-channel-current amplitude, selectivity among ions and open-channel blockade and is conserved in potassium-channel subunits previously recognized to contribute to pore formation. To date, potassium-channel pores have been shown to form by symmetrical alignment of four P loops around a central conduction pathway. Here we show that the selectivity-determining pore region of the voltage-gated potassium channel of human heart through which the I(Ks) current passes includes the transmembrane segment of the non-P-loop protein minK. Two adjacent residues in this segment of minK are exposed in the pore on either side of a short barrier that restricts the movement of sodium, cadmium and zinc ions across the membrane. Thus, potassium-selective pores are not restricted to P loops or a strict P-loop geometry.

Animals↗
PubMed2002

Clustering of neuronal potassium channels is independent of their interaction with PSD-95.

Voltage-dependent potassium channels regulate membrane excitability and cell-cell communication in the mammalian nervous system, and are found highly localized at distinct neuronal subcellular sites. Kv1 (mammalian Shaker family) potassium channels and the neurexin Caspr2, both of which contain COOH-terminal PDZ domain binding peptide motifs, are found colocalized at high density at juxtaparanodes flanking nodes of Ranvier of myelinated axons. The PDZ domain-containing protein PSD-95, which clusters Kv1 potassium channels in heterologous cells, has been proposed to play a major role in potassium channel clustering in mammalian neurons. Here, we show that PSD-95 colocalizes precisely with Kv1 potassium channels and Caspr2 at juxtaparanodes, and that a macromolecular complex of Kv1 channels and PSD-95 can be immunopurified from mammalian brain and spinal cord. Surprisingly, we find that the high density clustering of Kv1 channels and Caspr2 at juxtaparanodes is normal in a mutant mouse lacking juxtaparanodal PSD-95, and that the indirect interaction between Kv1 channels and Caspr2 is maintained in these mutant mice. These data suggest that the primary function of PSD-95 at juxtaparanodes lies outside of its accepted role in mediating the high density clustering of Kv1 potassium channels at these sites.

Animals↗
PubMed1998

Thiopental and propofol impair relaxation produced by ATP-sensitive potassium channel openers in the rat aorta.

ATP-sensitive potassium channel openers are used as vasodilators in the treatment of cardiovascular disorders. The effects of i.v. anaesthetics on arterial relaxation induced by ATP-sensitive potassium channel openers have not been studied. Therefore, in this study, we have examined if thiopental (thiopentone) and propofol affect the vascular response to the ATP-sensitive potassium channel openers, cromakalim and pinacidil, in the isolated rat aorta. Rings of rat thoracic aortas without endothelium were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative manner. During submaximal contractions with phenylephrine 0.3 mumol litre-1, relaxation after cromakalim 0.1-30 mumol litre-1, pinacidil 0.1-30 mumol litre-1 and papaverine 0.1-300 mumol litre-1 was demonstrated. Thiopental 30-300 mumol litre-1, propofol 10-100 mumol litre-1, 10% Intralipid 45 microliters or glibenclamide 5 mumol litre-1 were applied 15 min before addition of phenylephrine. During contractions with phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxation. A selective ATP-sensitive potassium channel antagonist, glibenclamide 5 mumol litre-1, abolished this relaxation, whereas it did not affect relaxation produced by papaverine. Thiopental concentrations > 30 mumol litre-1 significantly impaired relaxation produced by cromakalim or pinacidil. Propofol concentrations > 10 mumol litre-1 also significantly reduced relaxation produced by cromakalim or pinacidil, whereas Intralipid was ineffective. Thiopental 300 mumol litre-1 and propofol 100 mumol litre-1 did not alter relaxation produced by papaverine. These results suggest that the i.v. anaesthetics, thiopental and propofol, impaired vasodilatation mediated by ATP-sensitive potassium channels in vascular smooth muscle cells.

Adenosine Triphosphate↗
PubMed1996

Effects of potassium channel blockers on the action potentials and contractility of the rat right ventricle.

1. The effects of several potassium channel blockers on the action potentials and contractile force of the electrically driven rat right ventricle have been determined. 2. Glibenclamide, which blocks the ATP-sensitive potassium channels, had no effect on the ventricular action potentials or contractile force responses. 3. 4-Aminopyridine, which blocks the Na(+)-activated potassium channels in ventricles, at 0.3-3 mM increased the amplitude and prolonged the action potentials, and also augmented the force responses to cardiac stimulation and to isoprenaline. 4. Clofilium, a selective blocker of the delayed outward rectifying potassium channel, at 0.1 and 0.3 microM prolonged the action potentials. At 0.1 microM, clofilium augmented the cardiac stimulation responses and, at 0.3 microM, clofilium augmented the maximal responses to isoprenaline. At 1 and 3 microM, clofilium had a lesser ability to prolong action potentials and did not alter force responses. 5. Procaine blocks the Na(+)-activated and the delayed outward rectifying potassium channels and, at higher concentrations, sodium channels. Procaine, at 30 microM, prolonged the action potentials and augmented the force responses to isoprenaline, presumably by blocking potassium channels. Procaine, at 1 mM, had no effect on action potentials but reduced the maximal force responses to isoprenaline, probably by blocking sodium channels. 6. Tetraethylammonium blocks the inward rectifying and delayed outward rectifying potassium channels. Tetraethylammonium, at 1 and 3 mM, prolonged the action potentials and augmented all of the force responses; these effects are likely to be predominantly due to blocking the outward rectifying potassium channel. Thus, in the presence of procaine, the effects of tetraethylammonium are predominantly due to the additional blockade of the inward rectifying potassium channel and there were no effects. 7. None of the potassium channel blockers at any of the concentrations tested had arrhythmogenic effects alone or in the presence of isoprenaline. 8. In summary, this study has shown that blockade of the Na(+)-activated and the delayed outward rectifying, but not the ATP-sensitive or inward rectifying, potassium channel is associated with prolongation of the action potentials, augments the contractile force responses, and is not arrhythmogenic on the rat right ventricle. New drugs that block the Na(+)-activated or delayed outward rectifying potassium channel may have potential as positive inotropes in the treatment of heart failure.

4-Aminopyridine↗