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PubMed1994

Mg(2+)-dependent inward rectification of ROMK1 potassium channels expressed in Xenopus oocytes.

1. ROMK1 potassium channel currents were examined in Xenopus oocytes by two-microelectrode voltage-clamp and patch-clamp techniques following injection of oocytes with in vitro transcribed ROMK1 cRNA. Macroscopic currents recorded from intact cells rectified inwardly at positive potentials. 2. In inside-out membrane patches rectification is manifested as an apparent reduction of single channel current (at 500 Hz) in the presence of 0.1-10 mM Mg2+, without a decrease in the channel open probability. No inward rectification is observed when membrane patches are isolated into solutions containing potassium as the only internal inorganic cation. 3. Mg2+ block can be described by a simple one-site model for Mg2+ binding with K0 ([Mg2+] causing half-maximal block at 0 mV) of 16.7 mM and delta (the fraction of the membrane field sensed by the blocking Mg2+) of 0.35. 4. The voltage dependence of channel block by cytoplasmic Mg2+ was shifted approximately -50 mV by a reduction in extracellular [K+] from 140 to 0 mM, corresponding to a decrease of K0 to 4.4 mM. 5. At negative membrane potentials, ROMK1 channels exhibit a single subconducting state that is approximately 4/10 of the full conductance. The incidence of subconductance states is not appreciably enhanced in the presence of Mg2+.

Animals↗
PubMed1991

Potassium channel blockers inhibit D2 dopamine, but not A1 adenosine, receptor-mediated inhibition of striatal dopamine release.

D2 dopamine autoreceptors and A1 adenosine heteroreceptors inhibit the evoked release of dopamine from rat striatum. We examined the role of potassium channels in this modulation by determining the effects of two potassium channel blockers, 4-aminopyridine and tetraethylammonium, on the modulation of electrically stimulated release of endogenous dopamine from rat striatal slices. Maximally effective concentrations of the D2 dopamine receptor agonist N-0437 (10 nM) and of adenosine (50 microM) caused a 30% inhibition of evoked dopamine overflow, and their effects were additive. When coperfused with N-0437, both 4-aminopyridine and tetraethylammonium blocked the inhibition caused by N-0437 in a dose-dependent manner. 4-Aminopyridine was approximately three orders of magnitude more potent than tetraethylammonium, with complete blockade occurring at 3 microM and 1 mM, respectively. Binding experiments confirmed that neither 4-aminopyridine nor tetraethylammonium was a direct-acting D2 dopamine receptor antagonist at the concentration necessary to block the release-modulatory effect of D2 receptor activation. In contrast, the inhibitory modulation produced by adenosine was not affected by 4-aminopyridine (30 microM) or tetraethylammonium (1 mM). These results suggest that D2 dopamine and A1 adenosine receptors inhibit dopamine release in the striatum by different mechanisms. D2 dopamine autoreceptor action appears to involve potassium channels, whereas A1 adenosine receptor action does not.

4-Aminopyridine↗
PubMed1999

Functional consequences of a decreased potassium affinity in a potassium channel pore. Ion interactions and C-type inactivation.

Ions bound near the external mouth of the potassium channel pore impede the C-type inactivation conformational change (Lopez-Barneo, J., T. Hoshi, S. Heinemann, and R. Aldrich. 1993. Receptors Channels. 1:61- 71; Baukrowitz, T., and G. Yellen. 1995. Neuron. 15:951-960). In this study, we present evidence that the occupancy of the C-type inactivation modulatory site by permeant ions is not solely dependent on its intrinsic affinity, but is also a function of the relative affinities of the neighboring sites in the potassium channel pore. The A463C mutation in the S6 region of Shaker decreases the affinity of an internal ion binding site in the pore (Ogielska, E.M., and R.W. Aldrich, 1998). However, we have found that this mutation also decreases the C-type inactivation rate of the channel. Our studies indicate that the C-type inactivation effects observed with substitutions at position A463 most likely result from changes in the pore occupancy of the channel, rather than a change in the C-type inactivation conformational change. We have found that a decrease in the potassium affinity of the internal ion binding site in the pore results in lowered (electrostatic) interactions among ions in the pore and as a result prolongs the time an ion remains bound at the external C-type inactivation site. We also present evidence that the C-type inactivation constriction is quite local and does not involve a general collapse of the selectivity filter. Our data indicate that in A463C potassium can bind within the selectivity filter without interfering with the process of C-type inactivation.

Alanine↗
PubMed1997

The pore-lining region of shaker voltage-gated potassium channels: comparison of beta-barrel and alpha-helix bundle models.

Although there is a large body of site-directed mutagenesis data that identify the pore-lining sequence of the voltage-gated potassium channel, the structure of this region remains unknown. We have interpreted the available biochemical data as a set of topological and orientational restraints and employed these restraints to produce molecular models of the potassium channel pore region, H5. The H5 sequence has been modeled either as a tetramer of membrane-spanning beta-hairpins, thus producing an eight-stranded beta-barrel, or as a tetramer of incompletely membrane-spanning alpha-helical hairpins, thus producing an eight-staved alpha-helix bundle. In total, restraints-directed modeling has produced 40 different configurations of the beta-barrel model, each configuration comprising an ensemble of 20 structures, and 24 different configurations of the alpha-helix bundle model, each comprising an ensemble of 24 structures. Thus, over 1300 model structures for H5 have been generated. Configurations have been ranked on the basis of their predicted pore properties and on the extent of their agreement with the biochemical data. This ranking is employed to identify particular configurations of H5 that may be explored further as models of the pore-lining region of the voltage-gated potassium channel pore.

Amino Acid Sequence↗
PubMed2002

Interacting effects of N-terminal variation and strex exon splicing on slo potassium channel regulation by calcium, phosphorylation, and oxidation.

We have investigated the structural basis for the phenotype of a native rat Slo (rSlo) potassium channel (BK(Ca); KCNMA1) in a rat pituitary cell line, GH(4)C(1). Opposing regulation of these calcium- and voltage-activated potassium channels by cAMP- and cGMP-dependent protein kinases requires an alternatively spliced exon (strex) of 59 amino acids in the cytoplasmic C terminus of the pore-forming alpha subunit encoded by rslo. However, inclusion of this cysteine-rich exon produces a 10-fold increase in the sensitivity of the channels to inhibition by oxidation. Inclusion of the strex exon also increases channel sensitivity to stimulation by calcium, but responses in the physiological ranges of calcium and voltage require coassembly with beta(1) subunits. With strex present, however, beta(1) subunits only stimulated channels assembled from rSlo alpha subunits with a truncated N terminus beginning MDALI-. Thus N-terminal variation and strex exon splicing in rSlo interact to produce BK(Ca) channels with a physiologically relevant phenotype.

Adenosine Triphosphate↗
PubMed1995

Ryanodine induced block of a cloned human cardiac potassium channel.

The effects of ryanodine in a cloned human cardiac potassium channel (hKvl.5) expressed in a stable mouse L cell line was studied using whole cell voltage clamp technique. Ryanodine in a dose dependent manner (10(-7) - 10(-5) M) reduced the peak current as well as the current at the end of a 250 ms pulse. Dose response data fitted to a Hill equation yielded IC50 of 1.2 microM. The degree of block was not voltage dependent. Peak current was reduced from 43.6 +/- 12.5% at 10(-5) M to 11.3 +/- 4.8% at 10(-7) M ryanodine. Ryanodine reduced the tail current amplitude without changing the time course relative to the control. The inhibition was only partially reversible at concentrations below 10(-6) M.

Animals↗
PubMed2003

Mutation analysis of potassium channel genes KCNQ1 and KCNH2 in patients with long QT syndrome.

OBJECTIVE: To determine mutations of two common potassium channel subunit genes KCNQ1, KCNH2 causing long QT syndrome (LQTS) in the Chinese. METHODS: Thirty-one Chinese LQTS pedigrees were characterized for mutations in the two LQTS genes, KCNQ1 and KCNH2, by sequencing. RESULTS: Two novel KCNQ1 mutations, S277L in the S5 domain and G306V in the channel pore, and two novel KCNH2 mutations, L413P in the transmembrane domain S1 and L559H in the transmembrane domain S5 were identified. The triggering factors for cardiac events developed in these mutation carriers included physical exercise and excitation. Mutation L413P in KCNH2 was associated with the notched T wave on ECGs. Mutation L559H in KCNH2 was associated with the typical bifid T wave on ECGs. Mutation S277L in KCNQ1 was associated with a high-amplitude T wave and G306V was associated with a low-amplitude T wave. Two likely polymorphisms, IVS11 + 18C > T in KCNQ1 and L520V in KCNH2 were also identified in two LQTS patients. CONCLUSIONS: The mutation rates for both KCNQ1 (6.4%) and KCNH2 (6.4%) are lower in the Chinese population than those from North America or Europe.

Asian People↗
PubMed1993

A computational model of the HBK2 potassium channel ion pore.

A computational model of the putative ion pore region of the HBK2 potassium channel was developed. Utilizing experimentally derived constraints, conformations corresponding to both the open and closed states of the ion pore were determined. Also, a conformational basis for the different sensitivites of the internal and external tetraethylammonium binding sites has been proposed. The model presented here suggests a role for other regions of the HBK2 protein in determining the ion pore conformation.

Amino Acid Sequence↗
PubMed1993

Relaxant effects of the potassium channel activators BRL 38227 and pinacidil on guinea-pig and human airway smooth muscle, and blockade of their effects by glibenclamide and BRL 31660.

The airways relaxant effects and mechanism of action of the potassium channel activators BRL 38227 and pinacidil have been compared in guinea-pig and human airways. BRL 38227 was a potent relaxant in guinea-pig isolated trachealis (IC50 = 4.9 x 10(-7) M against spontaneous tone) and human isolated bronchi (IC50 = 4.75 x 10(-7) M against histamine-induced tone) and was eight- and six-fold more potent respectively than pinacidil. The relaxant effects of both compounds were shown to be markedly attenuated by glibenclamide (10(-5) M) and BRL 31660 (10(-5) M), with the nature of the blockade being species/tissue dependent. Glibenclamide (20 mg/kg iv) also inhibited the protective effects of BRL 38227 (50 micrograms/kg iv) and pinacidil (500 micrograms/kg iv) on histamine-induced changes in airways resistance and dynamic compliance in the anaesthetized guinea-pig, although the effects were short-lived. That both BRL 38227 and pinacidil owed their relaxant effects to potassium channel activation was supported by their ability to stimulate 42/43K efflux from guinea-pig trachealis preloaded with the radiotracer at concentrations of 10(-7) - 10(-5) M and 10(-5) M respectively. Pretreatment with either glibenclamide (10(-5) M) or BRL 31660 (10(-5) M) ablated the response to both compounds. These studies show that two mechanistically distinct potassium channel blockers, glibenclamide and BRL 31660, do not substantially differentiate between the actions of BRL 38227 and pinacidil, although differences do occur, particularly at high concentrations in vitro.

Animals↗
PubMed2003

Heteromeric Kv1 potassium channel expression: amino acid determinants involved in processing and trafficking to the cell surface.

Kv1.4 and Kv1.1 potassium channels are expressed in brain as mature glycoproteins that are trans-Golgi glycosylated. When expressed in cell lines these homomers had very different trans-Golgi glycosylation efficiencies and cell surface expression levels with Kv1.4 > Kv1.1 for both parameters (Zhu, J., Watanabe, I., Gomez, B., and Thornhill, W. B. (2001) J. Biol. Chem. 276, 39419-39427). This previous study identified determinants in the outer pore region of Kv1.4 and Kv1.1 that positively and negatively, respectively, affected these events when expressed as homomers. Here we investigated which subunit exhibited positive or negative effects on these processes when expressed as heteromers. Kv1.4/Kv1.1 heteromers, by coexpression or expression as tandem-linked heteromers, were expressed on the cell surface at approximately 20-fold lower levels versus Kv1.4 homomers but they were trans-Golgi glycosylated. The lower Kv1.4/Kv1.1 expression level was not rescued by Kvbeta 2.1 subunits. Thus Kv1.1 inhibited high cell surface expression and partially retained the heteromer in the endoplasmic reticulum, whereas Kv1.4 stimulated trans-Golgi glycosylation. The subunit determinants and cellular events responsible for these differences were investigated. In a Kv1.4/Kv1.1 heteromer, the Kv1.1 pore was a major negative determinant, and it inhibited high cell surface expression because it induced high partial endoplasmic reticulum retention and it decreased protein stability. Other Kv1.1 regions also inhibited high surface expression of heteromers. The Kv1.1 C terminus induced partial Golgi retention and contributed to a decreased protein stability, whereas the Kv1.1 N terminus contributed to only a decreased protein stability. Thus a neuron may regulate its cell surface K+ channel protein levels by different Kv1 subfamily homomeric and heteromeric combinations that affect intracellular retention characteristics and protein stability.

Amino Acid Sequence↗
PubMed1993

Pursuing the voltage sensor of a voltage-gated mammalian potassium channel.

Ion channels are generally classified as voltage- or ligand-gated channels based upon their ability to respond to a change in the transmembrane voltage or to a specific ligand interaction. The voltage sensor of voltage-gated ion channels is thought to be contained within the fourth putative transmembrane segment, S4, and is characterized by basic residues typically spaced apart. Thus far, a full understanding of all charges contributing to the voltage sensor of voltage-gated potassium channels has been lacking since several neutralization mutants in S4 could not be functionally expressed. By construction of multimeric cDNAs encoding a mammalian RCK1 (Kv1.1) potassium channel, we now report functional expression of all charge neutralizations in the S4 segment, providing a more comprehensive insight into the functioning of the voltage sensor.

Animals↗
PubMed1998

Cloning of a mammalian elk potassium channel gene and EAG mRNA distribution in rat sympathetic ganglia.

1. Three new members of the EAG potassium channel gene family were identified in rat and the complete coding sequence of one of these genes (elk1) was determined by cDNA cloning. 2. The elk1 gene, when expressed in Xenopus oocytes, encodes a slowly activating and slowly deactivating potassium channel. 3. The elk1 gene is expressed in sympathetic ganglia and is also expressed in sciatic nerve. 4. Six of the seven known EAG genes were found to be expressed in rat sympathetic ganglia, suggesting an important functional role for these channels in the sympathetic nervous system.

Animals↗
PubMed2005

Amino acids in the pore region of Kv1 potassium channels dictate cell-surface protein levels: a possible trafficking code in the Kv1 subfamily.

Kv1.1 and Kv1.4 potassium channels have different pore region determinants that were found to affect their cell-surface levels positively and negatively [Zhu, Watanabe, Gomez and Thornhill (2001) J. Biol. Chem. 276, 39419-39427; Zhu, Watanabe, Gomez and Thornhill (2003) J. Biol. Chem. 278, 25558-25567; Zhu, Watanabe, Gomez and Thornhill (2003) Biochem. J. 375, 761-768]. In the present study, we focused on the deep pore region of Kv1 members to test whether a cell-surface trafficking code was dictated by two amino acids. Kv1 channels with a threonine/lysine amino acid pair in a non-contiguous pore region promoted high surface levels, whereas a serine/tyrosine amino acid pair inhibited high surface expression by inducing a high level of partial endoplasmic reticulum retention. Our work suggests that a possible positive trafficking amino acid pair coding here for the Kv1 subfamily is Thr/Lys>Thr/Val>Thr/Tyr>Thr/Arg approximately Thr/His>Ser/Val>Ser/Tyr>Ser/Lys. The Kv1 trafficking code was not transferable to a Kv2 family member and thus it appears that it only governs surface levels in the context of its Kv1 native pore loop region and/or its S5 and S6 regions. All members of a given Kv2, Kv3 or Kv4 potassium channel subfamily have identical amino acids at similar positions in their deep pore regions (Thr/Tyr or Thr/Val), which suggests that any difference in surface levels among members is not dictated by these amino acids. Thus a major determinant for cell-surface trafficking of Kv1 potassium channels is an amino acid pair in their deep pore regions, whereas the cell-surface levels of a given Kv2, Kv3 or Kv4 subfamily member are probably not affected by these amino acids.

Amino Acid Sequence↗
PubMed1998

Ionisation behaviour and solution properties of the potassium-channel blocker ShK toxin.

The effects of pH, temperature and polypeptide concentration on the solution structure and side chain interactions of ShK toxin, a potassium-channel-blocking polypeptide from the sea anemone Stichodactyla helianthus, have been investigated by means of one-dimensional and two-dimensional 1H-NMR spectroscopy. Resonance assignments have been obtained for most protons in the molecule, and for the alpha and beta carbon atoms. The lack of concentration dependence of the 1H chemical shifts and linewidths indicates that self-association is not significant and cannot account for the sheet-like structure near the N terminus. The structure is stable to high temperature, showing little change even at 353 K. This stability allowed backbone-amide temperature coefficients to be interpreted, and the correlation of these values with hydrogen bonds observed in the structures and with solvent exchange rates is discussed. pKa values have been measured for Asp5, His19 and Tyr23, and the contributions to these pKa values from other residues investigated using the analogues R11Q (denoting substitution of Argll with Gln), R11E, H19K, K22A, Y23A and K30A. These results show that Asp5 (pKa 2.8) makes an electrostatic interaction with Lys30, which may be partially responsible for the importance of these side chains in the folding of synthetic toxin. The phenolic pKa of Tyr23 is reduced to 8.7 in the native toxin, as a result of interactions with the positively charged side chains of Arg11 and to a lesser extent Lys22. Several hydrogen bonds between the Arg11 guanidino group and the Tyr23 phenolic group are found in the solution structures. As these three residues are implicated in the tight binding of ShK toxin to the T-lymphocyte voltage-gated potassium channel Kv1.3, their close interactions should be taken into account in models of binding of this toxin to the pore and vestibule of this and other potassium channels.

Amino Acid Sequence↗
PubMed2004

The pharmacophore hypotheses of I(Kr) potassium channel blockers: novel class III antiarrhythmic agents.

Predictive pharmacophore models were developed for a large series of I(Kr) potassium channel blockers as class III antiarrhythmic agents using HypoGen in Catalyst software. The pharmacophore hypotheses were generated using a training set consisting of 34 compounds carefully selected from documents. Their biological data, expressed as IC(50), spanned from 1.5 nM to 2.8 mM with 7 orders difference. The most predictive hypothesis (Hypo1), consisting of four features (one positive ionizable feature, two aromatic rings and one hydrophobic group), had a best correlation coefficient of 0.825, a lowest rms deviation of 1.612, and a highest cost difference (null cost-total cost) of 77.552, which represents a true correlation and a good predictivity. The hypothesis Hypo1 was then validated by a test set consisting of 21 compounds and by a cross-validation of 95% confidence level with randomizing the data using CatScramble program. Accordingly, our model has strong predictivity to identify structural diverse I(Kr) potassium channel blockers with desired biological activity by virtual screening

Anti-Arrhythmia Agents↗
PubMed1995

Pinacidil relaxes porcine and human coronary arteries by activating ATP-dependent potassium channels in smooth muscle cells.

We investigated the effect of the potassium channel opener pinacidil on ATP-dependent K+ channels (KATP) in the relaxation of porcine and human coronary arteries by means of isometric contraction experiments in arterial rings. We also measured whole cell currents in freshly isolated porcine and human coronary artery vascular smooth muscle cells with patch clamp. We first characterized serotonin-induced precontractions in our vessels and proved that the contractions were mediated by Ca2+ influx through voltage-dependent Ca2+ channels. Similarly, we observed that serotonin-induced contractions were strongly enhanced by small K(+)-induced depolarizations. Pinacidil completely relaxed rings preconstricted with 5 microM serotonin and produced dose-dependent relaxations of 5 microM serotonin-preconstricted rings, with an IC50 of 1.26 microM. Similar results were observed (IC50 = 1.15 microM) when the endothelium was removed. The KATP blocker glibenclamide (3 microM), inhibited pinacidil-induced relaxations (5-10 microM) by approximately 25% although the KATP blocker tetrapentylammonium (10 microM), inhibited pinacidil-induced (5-10 microM) relaxations completely. Pinacidil 10 microM had only a minimal effect on rings precontracted with a 50 mM external K+ concentration (IC50 = 60 microM). Porcine and human arterial rings did not differ qualitatively in their responses. Moreover, in the patch clamp experiments pinacidil (1 microM and 20 microM) induced a large, nonrectifying, outward current in both human and porcine cells. The reversal potential was close to the K+ equilibrium potential, suggesting an induction of pinacidil-activated K+ current. The pinacidil-induced (1 microM) current was strongly inhibited by glibenclamide (3 microM). These data show that the relaxation of porcine and human coronary arteries by pinacidil is primarily induced by an opening of KATP in smooth muscle cells. Furthermore, the vasorelaxant effect of pinacidil is not endothelium dependent.

Animals↗
PubMed1996

Oxygen-induced constriction of rabbit ductus arteriosus occurs via inhibition of a 4-aminopyridine-, voltage-sensitive potassium channel.

The ductus arteriosus is a vital fetal structure allowing blood ejected from the right ventricle to bypass the pulmonary circulation in utero. Closure of the ductus arteriosus at birth, essential for postnatal adaptation, is initiated by an increase in oxygen (O2) tension. We recently demonstrated the presence of O2-sensitive potassium channels in the fetal and adult pulmonary circulation which regulate vascular tone in response to changes in O2 tension. In this study, we assessed the cellular mechanisms underlying O2-induced constriction of the ductus arteriosus in late-gestation fetal rabbits. We report that O2 reversibly inhibits a 58-pS voltage- and 4-aminopyridine-sensitive potassium channel, causing membrane depolarization, an increase in intracellular calcium through L-type voltage-gated calcium channels, and constriction of the ductus arteriosus. We conclude that the effector mechanism for O2 sensing in the ductus arteriosus involves the coordinated action of delayed rectifier potassium channels and voltage-gated calcium channels.

4-Aminopyridine↗