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PubMed2005

Two different conformational states of the KirBac3.1 potassium channel revealed by electron crystallography.

Potassium channels allow the selective flow of K(+) ions across membranes. In response to external gating signals, the potassium channel can move reversibly through a series of structural conformations from a closed to an open state. 2D crystals of the inwardly rectifying K(+) channel KirBac3.1 from Magnetospirillum magnetotacticum have been captured in two distinct conformations, providing "snap shots" of the gating process. Analysis by electron cryomicroscopy of these KirBac3.1 crystals has resulted in reconstructed images in projection at 9 A resolution. Kir channels are tetramers of four subunits arranged as dimers of dimers. Each subunit has two transmembrane helices (inner and outer). In one crystal form, the pore is blocked; in the other crystal form, the pore appears open. Modeling based on the KirBac1.1 (closed) crystal structure shows that opening of the ion conduction pathway could be achieved by bending of the inner helices and significant movements of the outer helices.

Amino Acid Sequence↗
PubMed2002

Potassium channels: gene family, therapeutic relevance, high-throughput screening technologies and drug discovery.

Existing drugs that modulate ion channels represent a key class of pharmaceutical agents across many therapeutic areas and there is considerable further potential for potassium channel drug discovery. Potassium channels represent the largest and most diverse sub-group of ion channels and they play a central role in regulating the membrane potential of cells. Recent advances in genomics have greatly added to the number of these potential drug targets, but selecting a suitable potassium channel for drug discovery research is a key step. In particular, the potential therapeutic relevance of a potassium channel should be taken into account when selecting a target for screening. Potassium channel drug discovery is being driven by a need to identify lead compounds that can provide tractable starting points for medicinal chemistry. Furthermore, advances in laboratory automation have brought significant opportunities to increase screening throughput for potassium channel assays, but careful assay configuration to model drug-target interactions in a physiological manner is an essential consideration. Several potassium channel screening platforms are described in this review in order to provide some insight into the variety of formats available for screening, together with some of their inherent advantages and limitations. Particular emphasis is placed on the mechanistic basis of drug-target interaction and those aspects of structure/function that are of prime importance in potassium channel drug discovery.

Animals↗
PubMed1992

Characterization of a Shaw-related potassium channel family in rat brain.

Previously, we characterized a Shaker-related family of voltage-gated potassium channels (RCK) in rat brain. Now, we describe a second family of voltage-gated potassium channels in the rat nervous system. This family is related to the Drosophila Shaw gene and has been dubbed Raw. In contrast to the RCK potassium channel family the Raw family utilizes extensive alternative splicing for expressing potassium channel subunits with variant C-termini. These alternative C-termini do not appear to influence the electrophysiological and pharmacological properties as studied in the Xenopus oocyte expression system. In situ hybridizations to sections of rat brain indicate that members of the Raw family are expressed in distinct areas of the central nervous system. Probably, Raw channels are expressed predominantly as homomultimers. Immunocytochemical experiments with antibodies against Raw3 and RCK4 proteins which form two distinct A-type potassium channels indicate that in hippocampus the two channels are expressed both in different neurons and in the same ones. In general, properties of Raw potassium channels appeared to be similar to RCK channels. However, Raw outward currents, in contrast to RCK currents, exhibit an intense rectification at test potentials higher than +20 to +40 mV. RCK and Raw channel subunits did not measurably coassemble into RCK/Raw heteromultimers after coinjecting RCK and Raw cRNA into Xenopus oocytes. These results suggest that members of the RCK and the Raw potassium channel families express potassium channels which form independent outward current systems. Combining the results of in situ hybridizations, immunocytochemical staining and expression of the cloned potassium channels in Xenopus oocytes demonstrates that unrestrained mixing of potassium channel subunits to form hybrid channels does not occur in the rat central nervous system. A single neuron is able to express multiple, independently assembled potassium channels.

Amino Acid Sequence↗
PubMed2003

Calcium-activated potassium channels: multiple contributions to neuronal function.

Calcium-activated potassium channels are a large family of potassium channels that are found throughout the central nervous system and in many other cell types. These channels are activated by rises in cytosolic calcium largely in response to calcium influx via voltage-gated calcium channels that open during action potentials. Activation of these potassium channels is involved in the control of a number of physiological processes from the firing properties of neurons to the control of transmitter release. These channels form the target for modulation for a range of neurotransmitters and have been implicated in the pathogenesis of neurological and psychiatric disorders. Here the authors summarize the varieties of calcium-activated potassium channels present in central neurons and their defining molecular and biophysical properties.

Aging↗
PubMed2003

Identification, synthesis, and activity of novel blockers of the voltage-gated potassium channel Kv1.5.

The voltage-gated potassium channel Kv1.5 is regarded as a promising target for the development of new atrial selective drugs with fewer side effects. In the present study the discovery of ortho,ortho-disubstituted bisaryl compounds as blockers of the Kv1.5 channel is presented. Several compounds of this new class were synthesized and screened for their ability to block Kv1.5 channels expressed in Xenopus oocytes. The observed structure-activity relationship (SAR) is described by a pharmacophore model that consists of three hydrophobic centers in a triangular arrangement. The hydrophobic centers are matched by a phenyl or pyridyl ring of the bisaryl core and both ends of the side chains. The most potent compounds (e.g., 17c and 17o) inhibited the Kv1.5 channel with sub-micromolar half-blocking concentrations and displayed 3-fold selectivity over Kv1.3 and no significant effect on the HERG channel and sodium currents. In addition, compounds 17c and 17m have already shown antiarrhythmic effects in a pig model.

Animals↗
PubMed1998

Cobatoxins 1 and 2 from Centruroides noxius Hoffmann constitute a subfamily of potassium-channel-blocking scorpion toxins.

Potassium-channel-blocking scorpion toxins (alpha-K-toxins) have been shown to be valuable tools for the study of potassium channels. Here we report two toxins, cobatoxin 1 and 2, of 32 amino acids, containing three disulphide bridges, that were isolated from the venom of the Mexican scorpion Centruroides noxius. Their primary sequences show less than 40% identity to other alpha-K-toxins. It is therefore proposed that they belong to subfamily 9. The cDNA of cobatoxin 1 encodes a putative signal peptide, a putative short propeptide, the mature peptide and two amino acids that are processed to leave cobatoxin 1 amidated at the C-terminus. In rat brain synaptosomal membranes cobatoxin 1 and cobatoxin 2 bind to a common binding site of alpha-K-toxins with Ki values of 109 pM and 87 pM, respectively. Moreover, they block the Shaker and Kv1.1 K+ channels with moderate affinities, with Kd values of around 0.7 microM and 4.1 microM (Shaker) and 0.5 microM and 1.0 microM (Kv1.1), respectively. A three-dimensional model of cobatoxin 1 was generated and used to interpret the obtained functional data on a structural basis.

Amino Acid Sequence↗
PubMedDate not supplied

Physiological roles and properties of potassium channels in corporal smooth muscle.

Decreased penile vascular resistance induced by corporal smooth muscle relaxation is the most important step in penile erection. The heightened tone of the corporal smooth muscles is considered a major cause in impotence. Modulation of corporal smooth muscle tone is a complex process requiring the integration of a host of intracellular events and extracellular signals. In intracellular events of corporal smooth muscle cell, the potassium channels and calcium channels play a major role. Functionally, potassium channels are important regulators of smooth muscle membrane potential in response to depolarizing stimuli and they counteract calcium channels. Potassium channels have been shown to play a fundamental role in both the physiologic and pathophysiologic regulation of smooth muscle tone in diverse tissues. Among the several subtypes of potassium channels, the calcium-sensitive (K(Ca)) or maxi-K potassium channel subtypes are thought to be the most physiologically relevant in human corporal smooth muscle. Because of the physiological role of maxi-K channels in human corporal smooth muscles, we investigated the maxi-K channels for the genetic therapy of erectile dysfunction. These data indicate that naked hSlo DNA of maxi-K channels is quite easily incorporated into corporal smooth muscle and expression of the maxi-K hSlo cDNA appeared to be sustained for 1-4 months postinjection. These results show the possibility of a similar genetic strategy of potassium channels in humans.

Journal Article↗
PubMed2004

Activation of the ATP-dependent potassium channel attenuates norepinephrine-induced vasoconstriction in the human forearm.

Sepsis-induced vasodilation is characterized by an attenuated sensitivity to vasoconstrictor substances such as norepinephrine, possibly mediated by activation of vascular potassium channels. We determined whether vasodilation associated with potassium channel activation resulted in an attenuated vasoconstrictive response to norepinephrine in humans and whether the vasodilation associated with potassium channel activation could be inhibited by pharmacological potassium channel blockers. In 30 volunteers, the brachial artery was cannulated for infusion of drugs. Forearm blood flow (FBF) was measured in both arms using strain-gauge venous occlusion plethysmography. Forearm vascular resistance (FVR, mean arterial pressure/FBF) was calculated. The effects of vasodilation induced by sodium nitroprusside (SNP, nitric oxide donor) or diazoxide (activator of the ATP-dependent potassium channel) on norepinephrine-mediated vasoconstriction were examined. Also, the effects of potassium channel blockers on vasodilation associated with potassium channel activation were determined. Intraarterial SNP infusion (2 microg/min/dL) increased forearm blood flow by 235%, from (mean +/- SEM) 2.8 +/- 0.7 to 9.4 +/- 1.5 mL/min/dL (P < 0.0001). Subsequent norepinephrine infusion (10, 30, 100, 300, 1000 ng/min/dL) increased FVR dose-dependently from 13 +/- 4 AU to 249 +/- 45 AU at the highest norepinephrine infusion. Intraarterial diazoxide infusion (1 mg/min/dL) increased FBF by 209% from 2.2 +/- 0.3 to 6.8 +/- 1.0 mL/min/dL (P < 0.001). Subsequent norepinephrine infusion increased FVR from 18 +/- 5 to 51 +/- 6 AU at the highest norepinephrine infusion rate (n = 10), significantly different from the norepinephrine-induced effects during SNP coinfusion (P < 0.001). Diazoxide-induced fall in FVR in the infused forearm was inhibited by potassium channel blockers tetraethyl ammonium (1 mg/min/dL, n = 10, P = 0.004) and quinine (50 microg/min/dL, n = 10, P = 0.016). Vasodilation induced by vascular potassium channel activation is associated with an impressive reduction in the vasoconstrictor response to norepinephrine in humans. In accordance with animal experiments, this indicates that potassium channel activation could account for the diminished norepinephrine sensitivity in septic patients. Vasodilation associated with potassium channel activation can be inhibited by pharmacological potassium channel blockade. The possible role of potassium channel blockers during sepsis-induced potassium channel activation and vasodilation in humans needs further elucidation.

Adult↗
PubMed1989

Interaction of potassium channel openers and blockers in canine atrial muscle.

1. The possibility that the interaction between potassium channel openers, e.g. cromakalim, pinacidil and nicorandil, and some potassium channel blockers involves a common site was investigated in canine atrial muscle. 2. Cromakalim, pinacidil and nicorandil produced a negative inotropic effect, their pD2 (-log EC50) values being 6.11 +/- 0.07, 5.37 +/- 0.09 and 4.55 +/- 0.07, respectively. 3. The potassium channel blockers, tetraethylammonium (TEA), tetrabutylammonium (TBA), 3,4-diaminopyridine (DAP), CsCl and BaCl2 all produced a positive inotropic effect. 4. The concentration-effect curves for the negative inotropic actions of pinacidil were shifted in a parallel way to the right by low concentrations of TEA, TBA or BaCl2. Maximum responses to pinacidil were depressed by higher concentrations of the blockers. An analysis of the non-competitive antagonism by TEA yielded pKA (-log KA) values of 4.00-4.05 for pinacidil. 5. The concentration-effect curves for cromakalim and nicorandil were shifted by TEA similarly to those for pinacidil, and a similar analysis yielded pKA values of 4.47-4.68 for cromakalim and 3.47-3.74 for nicorandil. 6. The KA values of cromakalim, pinacidil and nicorandil were about 10-30 times greater than their EC50 values, indicating that there are non-linear stimulus-effect relationships between the binding of the three potassium channel openers to their binding sites at potassium channels and their negative inotropic effects. 7. The dissociation constants for TEA could also be estimated from pA2 and pKB values for antagonizing competitively and non-competitively the negative inotropic effects of the three potassium channel openers; they were 3.47-3.89, and did not differ between the potassium channel openers. 8. The concentration-effect curves for the three potassium channel openers were not affected by DAP or CsCl. 9. These results suggest the following: (i) quaternary ammonium compounds like TEA and TBA antagonize the negative inotropic effect of cromakalim, pinacidil and nicorandil by binding to potassium channels, thus preventing binding of the channel openers to the same sites or closely related sites in canine right atrial muscles.

Animals↗
PubMed2003

Arranging the elements of the potassium channel: the T1 domain occludes the cytoplasmic face of the channel.

The voltage-gated potassium channel is currently one of the few membrane proteins where functional roles have been mapped onto specific segments of sequence. Although high-resolution structures of the transmembrane portions of three bacterial potassium channels, the tetramerization domain and the cytoplasmic "ball" are available, their relative spatial arrangement in mammalian channels remains a matter of ongoing debate. Cryo-electron microscopic images of the six transmembrane voltage-gated Kv channel have been reconstructed at up to 18 A resolution, revealing that the T1 domain tetramerizes and is suspended below the transmembrane segments. However, the resolution of these images is insufficient to reveal the location of the third piece of the puzzle, the inactivating ball domain. We have used the aberrant interactions observed in a series of chimaeric channels to establish that an assembled T1 domain restricts access to the cytoplasmic face of the channel, suggesting that the N-terminal "ball and chain" may be confined in the space between the T1 domain and the transmembrane portion of the channel.

Amino Acid Sequence↗
PubMed1997

Anionic phospholipids activate ATP-sensitive potassium channels.

The ATP-sensitive potassium channel (KATP) controls insulin release in pancreatic beta-cells and also modulates important functions in other cell types. In this study we report that anionic phospholipids activated KATP in pancreatic beta-cells, cardiac myocytes, skeletal muscle cells, and a cloned KATP composed of two subunits (SUR/Kir6. 2) stably expressed in a mammalian cell line. The effectiveness was proportional to the number of negative charges on the head group of the anionic phospholipid. Screening negative charges with polyvalent cations antagonized the effect. Enzymatic treatment with phospholipases that reduced charge on the lipids also reduced or eliminated the effect. These results suggest that intact phospholipids with negative charges are the critical requirement for activation of KATP, in distinction from the usual cell signaling pathway through phospholipids that requires cleavage. Mutations of two positively charged amino acid residues at the C terminus of Kir6. 2 accelerated loss of channel activity and reduced the activating effects of phospholipids, suggesting involvement of this region in the activation. Metabolism of anionic phospholipids in plasmalemmal membrane may be a novel and general mechanism for regulation of KATP and perhaps other ion channels in the family of inward rectifiers.

ATP-Binding Cassette Transporters↗
PubMed2000

Preconditioning with PKC and the ATP-sensitive potassium channels: a codependent relationship.

BACKGROUND: Both potassium channel openers and protein kinase C have been shown to independently elicit the myoprotective preconditioning response. However, the in vivo dependency between the two is unknown. METHODS: Thirty-seven sheep were divided into seven groups; animals received no pretreatment, pinacidil, pinacidil and potassium channel opener blocker glibenclamide, protein kinase C activator 4beta-phorbol-12,13-dibutyrate (PDBu), or PDBu and protein kinase C blocker chelerythrine. The last two groups underwent opposite blockade, chelerythrine + pinacidil, or glibenclamide + PDBu. All groups underwent 60 minutes of regional ischemia followed by 180 minutes of reperfusion. Regional function was assessed throughout the experiment, and at the conclusion of the study the infarct size (as a percentage of the area at risk) was determined. RESULTS: Infarct size decreased in the groups receiving only pinacidil or PDBu (control: 54%+/-3%, pinacidil: 25% +/-2%, PDBu: 21%+/-3%; p<0.05 pinacidil or PDBu versus control). This preconditioning protection was lost when the direct blocker was given (58%+/-5%, glibenclamide + pinacidil; 70%+/-6%, chelerythrine + PDBu; p = not significant versus control). The preconditioning response was again attenuated when the opposite blockers were given (64%+/-5%, chelerythrine + pinacidil; 63%+/-1%, glibenclamide + PDBu; p = not significant versus control). There was no significant difference in regional function. CONCLUSIONS: This study shows that both protein kinase C and potassium channels are necessary and codependent for preconditioning in the in vivo heart.

Animals↗
PubMed1997

Identification of two nervous system-specific members of the erg potassium channel gene family.

Two new potassium channel genes, erg2 and erg3, that are expressed in the nervous system of the rat were identified. These two genes form a small gene family with the previously described erg1 (HERG) gene. The erg2 and erg3 genes are expressed exclusively in the nervous system, in marked contrast to erg1, which is expressed in both neural and non-neural tissues. All three genes are expressed in peripheral sympathetic ganglia. The erg3 channel produces a current that has a large transient component at positive potentials, whereas the other two channels are slowly activating delayed rectifiers. Expression of the erg1 gene in the sympathetic nervous system has potential implications for the etiology of the LQT2 form of the human genetic disease long QT syndrome.

Animals↗
PubMed2002

Role of endothelial nitric oxide and smooth muscle potassium channels in cerebral arteriolar dilation in response to acidosis.

BACKGROUND AND PURPOSE: Potassium channels or nitric oxide or both are major mediators of acidosis-induced dilation in the cerebral circulation. However, these contributions depend on a variety of factors such as species and vessel location. The present study was designed to clarify whether potassium channels and endothelial nitric oxide are involved in acidosis-induced dilation of isolated rat cerebral arterioles. METHODS: Cerebral arterioles were cannulated and monitored with an inverted microscope. Acidosis (pH 6.8 to 7.4) produced by adding hydrogen ions mediated dilation of the cerebral arterioles in a concentration-dependent manner. The role of nitric oxide and potassium channels in response to acidosis was examined with several specific inhibitors and endothelial damage. RESULTS: The dilation was significantly inhibited by potassium chloride (30 mmol/L) and glibenclamide (3 micromol/L; ATP-sensitive potassium channel inhibitor). We found that 30 micromol/L BaCl2 (concentration-dependent potassium channel inhibitor) also affected the dilation; however, an additional treatment of 3 micromol/L glibenclamide did not produce further inhibition. Tetraethylammonium ion (1 mmol/L; calcium-activated potassium channel inhibitor) and 4-aminopyridine (100 micromol/L; voltage-dependent potassium channel inhibitor) as well as ouabain (10 micromol/L; Na-K ATPase inhibitor) and N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (1 micromol/L; cytochrome P450 epoxygenase inhibitor) did not alter acidotic dilation. N(omega)-Monomethyl-L-arginine (10 micromol/L) and N(omega)-nitro-L-arginine (10 micromol/L) as nitric oxide synthase inhibitor blunted the dilation. Furthermore, the dilation was significantly attenuated after the endothelial impairment. Additional treatment with glibenclamide (3 micromol/L) further reduced the dilation in response to acidosis. CONCLUSIONS: Endothelial nitric oxide and smooth muscle ATP-sensitive potassium channels contribute to acidosis-induced dilation of rat cerebral arterioles. Endothelial damage caused by pathological conditions such as subarachnoid hemorrhage or traumatic brain injury may contribute to reduced blood flow despite injury-induced cerebral acidosis.

Acidosis↗
PubMed2002

Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes.

Several potassium channel genes have been implicated in epilepsy. We have investigated three such genes, KCNJ3, KCNJ6 and KCNQ2, by association studies using a broad sample of idiopathic generalised epilepsy (IGE) unselected by syndrome. One of the two single nucleotide polymorphisms (SNPs) examined in one of the inward rectifying potassium channel genes, KCNJ3, was associated with IGE by genotype (P=0.0097), while its association by allele was of borderline significance (P=0.051). Analysis of the different clinical subgroups within the IGE sample showed more significant association with the presence of absence seizures (P=0.0041) and which is still significant after correction for multiple testing. Neither SNP in the other rectifying potassium channel gene, KCNJ6, was associated with IGE or any subgroup. None of the three SNPs in the voltage-gated potassium channel gene, KCNQ2, was associated with IGE. However, one SNP was associated with epilepsy with generalised tonic clonic seizures only (P=0.016), as was an SNP approximately 56 kb distant in the closely linked nicotinic acetylcholine gene CHRNA4 (P=0.014). These two SNPs were not in linkage disequilibrium with each other, suggesting that if they are not true associations they have independently occurred by chance. Neither association remains significant after correcting for multiple testing.

3' Untranslated Regions↗
PubMed2004

Levosimendan interacts with potassium channel blockers in human saphenous veins.

The involvement of potassium channels in the venodilating capacity of the inodilator levosimendan in human saphenous vein preparations was investigated. Levosimendan caused relaxation with 50% effective concentration (EC50) of 0.32 +/- 0.04 microM in isolated veins contracted by 5-hydroxytryptamine. Fifteen microM glibenclamide, a blocker of the ATP-sensitive potassium channels (K(ATP)), partially inhibited the relaxing effect of the inodilator. In the presence of iberiotoxin, the selective blocker of large conductance calcium-activated potassium channels (BK(Ca)), levosimendan induced contraction with EC50 of 0.21 +/- 0.06 microM. We presume that levosimendan dilates human saphenous veins by interacting with hyperpolarizing potassium channels (K(ATP) and BK(Ca)).

Drug Interactions↗
PubMed2002

Functional distinction of human EAG1 and EAG2 potassium channels.

Human ether à go-go potassium channel 2 (hEAG2) was cloned and its properties were compared with the previously characterized isoform hEAG1. In the Xenopus oocyte expression system the time course of activation was about four times slower and the voltage required for half-maximal subunit activation was about 10 mV greater for hEAG2 channels. However, its voltage dependence was smaller and, therefore, hEAG2 channels start to open at more negative voltages than hEAG1. Coexpression of both isoforms and kinetic analysis of the resulting currents indicated that they can form heteromeric channel complexes in which the slow activation phenotype of hEAG2 is dominant. Upon expression in mammalian cells, quinidine blocked hEAG1 channels (IC(50) 1.4 microM) more potently than hEAG2 channels (IC(50) 152 microM), thus providing a useful tool for the functional distinction between hEAG1 and hEAG2 potassium channels.

Animals↗
PubMedDate not supplied

Structural basis of potassium channel diversity in the nervous system.

A variety of voltage-sensitive potassium channels has been described which differ in their electrophysiological and pharmacological properties. Potassium channels which mediate outward K+ currents in response to changes in membrane polarisation differ most notably in their voltage sensitivity and their opening and closing kinetics, as well as their recovery times from inactivation. Also, some of these potassium channels are sensitive to toxins like dendrotoxin and mast cell degranulating peptide; others are not. We have cloned and sequenced a variety of cDNAs encoding potassium channel subunits present in invertebrate as well as vertebrate central nervous systems. Injection into Xenopus oocytes of RNA synthesized in vitro using the various cDNAs as a template results in the expression of functional potassium channels. Some of these channels exhibit properties similar to those of the non-inactivating delayed rectifier channel found in many excitable cells, yet differ in their sensitivities towards potassium channel blocking agents. The properties of other channels expressed from cRNA injected into Xenopus oocytes resemble those of transient A-type channels which inactivate rapidly after opening upon membrane depolarisation. A comparison of the derived primary sequences of the different potassium channels allows a direct correlation of channel protein structures with electrophysiological and pharmacological properties, respectively.

Animals↗